The Clinical Relevance of Diabetes Distress versus Major Depression in Type 2 Diabetes: A Latent Class Analysis from the Fremantle Diabetes Study Phase II.

BACKGROUND: The nosological position and clinical relevance of the concept of diabetes distress (DD) are uncertain. The aim of this study was to use latent class analysis (LCA) to categorise classes of people with type 2 diabetes and to compare their characteristics. METHODS: Data from 662 participants in the longitudinal observational Fremantle Diabetes Study Phase II were analysed. LCA identified latent subgroups based on individual responses to the Patient Health Questionnaire-9, the Generalised Anxiety Disorder Scale, and the 5-item Problem Areas in Diabetes Scale. RESULTS: Four classes were identified: Class 1 (65.7%, no symptoms), Class 2 (14.0%, DD), Class 3 (12.6%, subsyndromal depression (SSD)), and Class 4 (7.6%, major depression (MD)). Multinomial regression analysis with Class 1 as reference showed significant associations between the DD class and Southern European and Asian ethnic background, HbA1c, and BMI. The SSD class was significantly associated with HbA1c, cerebrovascular disease, and coronary heart disease (CHD). The MD class had significant associations with age (inversely), Southern European ethnic background, HbA1c, BMI, and CHD. In conclusion, LCA identified a pure DD group comprising 14.0% of participants. The only variable uniquely associated with the DD class was Asian ethnic background. CONCLUSION: Although identification of DD may have some utility in assessing the psychological wellbeing of individuals with type 2 diabetes, it adds little to the assessment of depressive disorder and its significant clinical sequalae.

Group-Based Trajectory Modelling of Changes in Mobility over Six Years in Type 2 Diabetes: The Fremantle Diabetes Study Phase II.

To investigate temporal changes in mobility in community-based people with type 2 diabetes, Fremantle Diabetes Study Phase II (FDS2) data were analysed. The baseline assessment included the Timed Up and Go (TUG) test, which was repeated biennially for up to six years. Group-based trajectory modelling (GBTM) identified TUG trajectory groups in participants with ≥2 tests. Independent associates of group membership were assessed using multinomial regression. Of 1551 potential FDS2 participants, 1116 (72.0%; age 64.9 ± 11.0 years, 45.6% female) were included in the modelling. The best-fitting GBTM model identified two groups with linear, minimally changing trajectories (76.2% and 19.4% of participants; baseline TUG times 8 ± 2 and 12 ± 3 s, respectively), and a third (4.5%; baseline TUG 17 ± 5 s) with a TUG that increased over time then fell at Year 6, reflecting participant attrition. Both slower groups were older, more likely to be female, obese, and had greater diabetes-associated complications and comorbidities. Almost one-quarter of the FDS2 cohort had clinically relevant mobility impairment that persisted or worsened over six years, was multifactorial in origin, and was associated with excess late withdrawals and deaths. The TUG may have important clinical utility in assessing mobility and its consequences in adults with type 2 diabetes.

The relationship between thyroid dysfunction, cardiovascular morbidity and mortality in type 2 diabetes: The Fremantle Diabetes Study Phase II.

AIMS: It is uncertain whether subclinical thyroid dysfunction is associated with cardiovascular disease (CVD) events and mortality in people with type 2 diabetes. The aim of this study was to determine whether undetected thyroid disease increases the risk of incident CVD and death in type 2 diabetes. METHODS: One thousand two hundred fifty participants with type 2 diabetes (mean age 65.3 years, 56.5% males, median diabetes duration 8.0 years) without known thyroid disease and not taking medications known to affect thyroid function were categorised, based on baseline serum free thyroxine (FT4) and thyrotropin (TSH) concentrations, as euthyroid, overt hypothyroid (increased TSH, low FT4), subclinical hypothyroid (increased TSH, normal FT4), overt thyrotoxic (decreased TSH, raised FT4) or subclinical thyrotoxic (decreased TSH, normal FT4). Incident myocardial infarction, incident stroke, all-cause and cardiovascular mortality were ascertained during a mean 6.2-6.7 years of follow-up. RESULTS: Most participants with newly-detected thyroid dysfunction had subclinical hypothyroidism (77.2%) while overt/subclinical thyrotoxicosis was infrequent. Compared to participants with TSH 0.34-2.9 mU/L, those with TSH > 5.1 mU/L were not at increased risk of incident myocardial infarction (adjusted hazard ratio (95% confidence limits) 1.77 (0.71, 2.87)), incident stroke (1.66 (0.58, 4.78)), all-cause mortality (0.78 (0.44, 1.37)) or cardiovascular mortality (1.16 (0.38, 3.58)). Independent baseline associates of subclinical hypothyroidism included estimated glomerular filtration rate and systolic blood pressure. CONCLUSIONS: Subclinical hypothyroidism was not independently associated with CVD events or mortality in community-dwelling people with type 2 diabetes despite its associations with CVD risk factors, questioning strategies to identify and/or treat mild thyroid dysfunction outside usual care.

Temporal Trends in Mortality Associated with Comorbid Type 2 Diabetes and Schizophrenia: The Fremantle Diabetes Study.

BACKGROUND: In Phase I of the community-based Fremantle Diabetes Study (FDS1), there was evidence of a deleterious interactive effect of schizophrenia and type 2 diabetes on mortality. Our aim was to investigate whether the mortality gap had improved in FDS Phase II (FDS2) conducted 15 years later. METHODS: Participants with type 2 diabetes from FDS1 (n = 1291 recruited 1993-1996) and FDS2 (n = 1509 recruited 2008-2011) were age-, sex- and postcode-matched 1:4 to people without diabetes. Schizophrenia at entry and incident deaths were ascertained from validated administrative data. RESULTS: Schizophrenia affected 50/11,195 (0.45%) of participants without diabetes and 17/2800 (0.61%) of those with type 2 diabetes (p = 0.284). During 142,304 person-years of follow-up, the mortality rate (95% CI) was lowest for the FDS2 subgroup without diabetes/schizophrenia (18.2 (16.9, 19.6)/1000 person-years) and highest in FDS2 and FDS1 subgroups with type 2 diabetes/schizophrenia (53.3 (14.5, 136.6) and 98.0 (31.8, 228.8)/1000 person-years, respectively). Compared to the respective FDS subgroup without diabetes/schizophrenia, the mortality rate ratio was approximately 50% higher in the type 2 diabetes subgroup, and three times higher in those with type 2 diabetes/schizophrenia. In Cox regression, unadjusted hazard ratios were highest in those with type 2 diabetes/schizophrenia in FDS1 (HR (95% CI): 3.71 (1.54, 8.93) and FDS2 (2.96 (1.11, 7.91)), increasing to 5.61 (2.33, 13.5) and 26.9 (9.94, 72.6), respectively, after adjustment for age. CONCLUSIONS: Although limited by small numbers of schizophrenia cases, these data suggest that comorbid type 2 diabetes and schizophrenia remains associated with a substantial and possibly increasing mortality gap.

Prevalence and patterns of multimorbidity in Australian baby boomers: the Busselton healthy ageing study.

BACKGROUND AND OBJECTIVE: Chronic medical conditions accumulate within individuals with age. However, knowledge concerning the trends, patterns and determinants of multimorbidity remains limited. This study assessed the prevalence and patterns of multimorbidity using extensive individual phenotyping in a general population of Australian middle-aged adults. METHODS: Participants (n = 5029, 55% female), born between 1946 and 1964 and attending the cross-sectional phase of the Busselton Healthy Ageing Study (BHAS) between 2010 and 2015, were studied. Prevalence of 21 chronic conditions was estimated using clinical measurement, validated instrument scores and/or self-reported doctor-diagnosis. Non-random patterns of multimorbidity were explored using observed/expected (O/E) prevalence ratios and latent class analysis (LCA). Variables associated with numbers of conditions and class of multimorbidity were investigated. RESULTS: The individual prevalence of 21 chronic conditions ranged from 2 to 54% and multimorbidity was common with 73% of the cohort having 2 or more chronic conditions. (mean ± SD 2.75 ± 1.84, median = 2.00, range 0-13). The prevalence of multimorbidity increased with age, obesity, physical inactivity, tobacco smoking and family history of asthma, diabetes, myocardial infarct or cancer. There were 13 pairs and 27 triplets of conditions identified with a prevalence > 1.5% and O/E > 1.5. Of the triplets, arthritis (> 50%), bowel disease (> 33%) and depression-anxiety (> 33%) were observed most commonly. LCA modelling identified 4 statistically and clinically distinct classes of multimorbidity labelled as: 1) "Healthy" (70%) with average of 1.95 conditions; 2) "Respiratory and Atopy" (11%, 3.65 conditions); 3) "Non-cardiometabolic" (14%, 4.77 conditions), and 4) "Cardiometabolic" (5%, 6.32 conditions). Predictors of multimorbidity class membership differed between classes and differed from predictors of number of co-occurring conditions. CONCLUSION: Multimorbidity is common among middle-aged adults from a general population. Some conditions associated with ageing such as arthritis, bowel disease and depression-anxiety co-occur in clinically distinct patterns and at higher prevalence than expected by chance. These findings may inform further studies into shared biological and environmental causes of co-occurring conditions of ageing. Recognition of distinct patterns of multimorbidity may aid in a holistic approach to care management in individuals presenting with multiple chronic conditions, while also guiding health resource allocation in ageing populations.

Cognitive Impairment in People with Diabetes-Related Foot Ulceration.

AIMS: To determine whether there is an excess of cognitive impairment in patients with type 2 diabetes and foot ulceration. METHODS: 55 patients with type 2 diabetes and foot ulcers attending Multidisciplinary Diabetes Foot Ulcer clinics (MDFU cohort) were compared with 56 patients with type 2 diabetes attending Complex Diabetes clinics (CDC cohort) using commonly used screening tests for cognitive impairment (Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MOCA)), as well as foot self-care, mood and health literacy. MMSE was also compared between the MDFU cohort and a historical community-based cohort of patients with type 2 diabetes (FDS2 cohort). RESULTS: Median MMSE scores were the same in all three groups (28/30). Median MOCA scores did not differ between the MDFU and CDC cohorts (25/30). There were no significant differences in the percentages of patients with MMSE ≤ 24 or MOCA ≤ 25 between MDFU and CDC cohorts (3.6% versus 10.7%, p = 0.27 and 56.4% versus 51.8%, p = 0.71, respectively), findings that did not change after adjustment for age, sex, education, diabetes duration, and random blood glucose. CONCLUSIONS: Using conventionally applied instruments, patients with type 2 diabetes and foot ulceration have similar cognition compared with patients without, from either hospital-based clinic or community settings.

Contemporary Cardiovascular Risk Assessment for Type 2 Diabetes Including Heart Failure as an Outcome: The Fremantle Diabetes Study Phase II.

Background: Type 2 diabetes (T2D) cardiovascular disease (CVD) risk assessment has limitations. The aim of this study was to develop a risk equation adding heart failure (HF) to conventional major adverse cardiovascular events (MACE, myocardial infarction, stroke, and CVD death) and allowing for non-CVD death. Methods: 1551 community-based people with T2D (mean age 66 years, 52% males) were followed from baseline in 2008-2011 for five years to the first CVD event/death. Cox and competing risk regression identified predictors of three-point MACE and four-point MACE (including HF). Discrimination was assessed by the area under the receiver-operating characteristic curve (AUC) and calibration by the Hosmer-Lemeshow test. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined for a 10% five-year CVD risk cut-off. Results: 143 participants (9.2%) experienced a three-point MACE during 7,111 person-years of follow-up and 245 (15.8%) a four-point MACE during 6,896 person-years. The best model was the competing risk four-point MACE (221 predicted events (14.3%), AUC 0.82 (95% CI: 0.79-0.85), Hosmer-Lemeshow test, p = 0.17, sensitivity 79.2%, specificity 68.1%, PPV 31.8%, NPV 94.6%) with validation in 177 adults with T2D from an independent population (AUC 0.81 (0.74-0.89). Conclusions: A validated four-point MACE competing risk model reliably predicts key T2D CVD outcomes.

Retinopathy predicts stroke but not myocardial infarction in type 2 diabetes: the Fremantle Diabetes Study Phase II.

BACKGROUND: Microangiopathy in type 2 diabetes (T2D) is associated with cardiovascular disease (CVD), but most relevant studies were performed > 10 years ago. CVD risk factor management has since improved. The aim of this study was to determine whether diabetic retinopathy (DR) and its severity increases stroke and myocardial infarction (MI) risk in a contemporary cohort. METHODS: Fremantle Diabetes Study Phase II participants with T2D had DR graded from fundus photography at baseline between 2008 and 2011. Subsequent hospitalizations and mortality for MI or stroke were ascertained through validated data linkage to end-2016. Cox regression modelling identified predictors of first stroke and MI including DR presence and severity. RESULTS: The 1521 participants with T2D and known DR status (mean age 65.6 years, 52.1% males, median diabetes duration 9.0 years) were followed for a mean of 6.6 years. After excluding those with prior MI/stroke, there were 126 incident MIs among 1393 eligible participants and 53 incident strokes in 1473 eligible participants, respectively. Moderate non-proliferative DR (NPDR) or worse was significantly and independently associated with an increased risk of incident stroke (adjusted hazard ratio 2.55 (95% CI 1.19, 5.47), p = 0.016). Retinopathy presence and severity increased the risk of incident MI in unadjusted models (p ≤ 0.001), but these associations were no longer statistically significant after adjusting for other risk factors. CONCLUSIONS: Moderate NPDR or worse was associated with an increased risk of first stroke in Australians with T2D. Intensified CVD risk factor management should be considered for patients with at least moderate NPDR.

Prevalence and incidence of thyroid dysfunction in type 1 diabetes, type 2 diabetes and latent autoimmune diabetes of adults: The Fremantle Diabetes Study Phase II.

OBJECTIVE: Since the results of published studies assessing thyroid dysfunction complicating diabetes have been variable in quality, inconsistent and may not reflect contemporary clinical care, the aim of this study was to determine its prevalence and incidence in a large, well-characterized, representative cohort. DESIGN: Community-based, longitudinal, observational study. PATIENTS: A total of 1617 participants from the Fremantle Diabetes Study Phase II (FDS2), including 130 (8.0%) with type 1 diabetes, 1408 (87.1%) with type 2 diabetes, and 79 (4.9%) with latent autoimmune diabetes of adults (LADA). MEASUREMENTS: Serum thyrotropin (TSH) and free thyroxine (FT4) at baseline between 2008 and 2011 and in those attending Year 4 follow-up. RESULTS: The prevalence of known thyroid disease (ascertained from baseline self-reported thyroid medication use or hospitalization data) was 11.7% (189/1617). Of the remaining 1428 participants, 5.1% (73/1428) had biochemical evidence of subclinical hypothyroidism, 1.1% (15/1428) overt hypothyroidism, 0.1% (2/1428) subclinical hyperthyroidism and 0.2% (3/1428) overt hyperthyroidism, representing an overall baseline prevalence of thyroid disease of 17.4% (282/1617). During 5694 patient-years of follow-up, 25 (3.0%) of the 844 with a normal baseline TSH and follow-up data developed known thyroid disease. Of the remaining 819, 3.4% developed subclinical hypothyroidism, 0.2% overt hypothyroidism and 0.5% subclinical hyperthyroidism. There were no statistically significant differences in the prevalence or incidence of thyroid dysfunction by diabetes type. CONCLUSIONS: Thyroid dysfunction, known or detected through screening, is common in diabetes. These data suggest the need for periodic clinical and biochemical screening for thyroid disease in all types of diabetes.

A comparison of obesity indices in relation to mortality in type 2 diabetes: the Fremantle Diabetes Study.

AIMS/HYPOTHESIS: This prospective association study aimed to compare the relationship between each of four obesity indices and mortality risk in people with type 2 diabetes. METHODS: The associations of BMI, waist circumference, WHR and A Body Shape Index (ABSI) with all-cause mortality were analysed in 1282 participants of the Fremantle Diabetes Study, followed for up to 20 years after baseline assessment. Models were adjusted for age and other confounders; assessments as continuous measures and by quintile were carried out for men and women separately. Sensitivity analyses were conducted to minimise reverse causality. RESULTS: When indices were assessed as continuous variables, there were significant bivariate associations with mortality for: ABSI, which was greater in both men and women who died (p < 0.001); WHR, which was greater in women only (p = 0.033); and BMI, which was lower in women only (p < 0.001). When assessed by quintile, there were significant bivariate associations with mortality for ABSI in men and women (p < 0.001) and BMI in women only (p = 0.002). In Cox models of time to death, adjusted for age, diabetes duration, ethnicity and smoking, ABSI quintiles showed a linear trend for both men (p = 0.003) and women (p = 0.035). Men in the fifth ABSI quintile had an increased mortality risk compared with those in the first quintile (HR [95% CI]: 1.74 [1.24, 2.44]) and women in the fifth ABSI quintile had an increased mortality risk that approached statistical significance (1.42 [0.97, 2.08], p = 0.08). Men in the fifth WHR quintile had an increased mortality risk (1.47 [1.05, 2.06]). There was no association between mortality and BMI or waist circumference in either sex. CONCLUSIONS/INTERPRETATION: ABSI was the obesity index most strongly associated with all-cause mortality in Australians with type 2 diabetes. There was no evidence for an obesity paradox with any of the assessed indices. ABSI may be a better index of central obesity than waist circumference, BMI or WHR when assessing mortality risk in type 2 diabetes.

Subjective memory complaints are not increased in type 2 diabetes: A matched cohort study.

Type 2 diabetes is associated with several cognitive syndromes but whether this generates subjective complaints remains unclear. In an age- and sex-matched study, subjective memory complaints were neither more prevalent nor more severe in those with type 2 diabetes, despite them having lower Mini-Mental State Examination scores.

Dementia complicating type 2 diabetes and the influence of premature mortality: the Fremantle Diabetes Study.

AIMS: To investigate risk factors for, and the influence of premature mortality on, dementia complicating type 2 diabetes. METHODS: Participants with type 2 diabetes in the community-based observational Fremantle Diabetes Study Phase 1 (n = 1291, mean age 64.0 years) were followed from 1993 to 1996 to end-June 2012. Incident dementia was identified from validated health databases. Dementia risk was assessed using Cox proportional hazards modelling supplemented by competing risk regression modelling in the total cohort and sub-groups defined by age of diabetes onset as mid-life (< 65 years) or late-life (≥ 65 years). RESULTS: During mean ± SD follow-up of 12.7 ± 5.9 years, 717 participants (55.5%) died and 180 (13.9%) developed dementia. Overall, few risk factors predicted incident dementia and most predicted time to death. In mid-life diabetes, incident dementia was predicted by diabetes duration, cerebrovascular disease, schizophrenia, antipsychotic medication and the APOE ε4 allele. In late-life diabetes, risk factors were peripheral neuropathy, lack of exercise, lower fasting serum glucose, no antihypertensive therapy and the APOE ε4 allele. Competing risk analysis showed age to be a positive predictor compared with the inverse association in Cox models that suggested survivor bias in an older community-based cohort. CONCLUSIONS: Dementia in type 2 diabetes is multifactorial. An association with diabetes duration, independent of most possible confounders, suggests that one or more unmeasured processes specific to diabetes may be implicated in the pathogenesis. The risk factors for dementia were also associated with an increased risk of death. This suggests that recently reported improvements in mortality in type 2 diabetes may be accompanied by reductions in dementia incidence.

Temporal changes in the incidence and predictors of severe hypoglycaemia in type 2 diabetes: The Fremantle Diabetes Study.

AIM: To determine the incidence of severe hypoglycaemia and its predictors in community-based patients with type 2 diabetes studied between 2008 and 2013 compared with those in a cohort of patients with type 2 diabetes from the same geographical area assessed a decade earlier. METHODS: We studied 1551 participants (mean age 65.7 years, 51.9% men) with type 2 diabetes from the longitudinal observational Fremantle Diabetes Study Phase II (FDS2). Severe hypoglycaemia was ascertained as that requiring ambulance attendance, emergency department services and/or hospitalization. Cox proportional hazards modelling was used to determine predictors of a first episode of severe hypoglycaemia, and negative binomial regression was used to identify predictors of frequency. RESULTS: Sixty-three participants (4.1%) experienced 83 episodes, representing an incidence of 1.34/100 participant-years (95% confidence interval [CI] 1.08 to 1.67; vs 1.67/100 participant-years [95% CI 1.31-2.13] in the Fremantle Diabetes Study Phase I [FDS1]; P = 0.18). Those experiencing severe hypoglycaemia experienced one to four episodes in both cohorts. The independent predictors of incident severe hypoglycaemia in the FDS2 were: older age; higher educational attainment; alcohol consumption; current smoking; sulphonylurea/insulin treatment; prior severe hypoglycaemia; renal impairment; and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP). The same variables except smoking were associated with frequency of severe hypoglycaemia. Most of these risk factors paralleled those in the FDS1, but current smoking and plasma NT-proBNP were novel. CONCLUSIONS: The incidence and frequency of severe hypoglycaemia did not change between the Fremantle Diabetes Study phases but novel risk factors, including plasma NT-proBNP, were observed in the FDS2.

Development and Validation of a Simple Hip Fracture Risk Prediction Tool for Type 2 Diabetes: The Fremantle Diabetes Study Phase I.

OBJECTIVE: To develop a type 2 diabetes hip fracture risk tool in community-based patients, to validate it in an independent cohort, and to compare its performance against the only published prediction equation to include type 2 diabetes as a risk factor (QFracture). RESEARCH DESIGN AND METHODS: Hip fracture hospitalizations in 1,251 participants with type 2 diabetes aged 40-89 years from the longitudinal Fremantle Diabetes Study Phase I (FDS1) were ascertained between entry (1993-1996) and end-2012. Competing risk regression modeling determined independent predictors of time to first fracture over 10 years and the coefficients incorporated in a risk model. The model was validated in 286 participants with type 2 diabetes from the Busselton Health Study (BHS). RESULTS: Fifty FDS1 participants (4.0%) experienced a first hip fracture during 10,306 person-years of follow-up. Independent predictors of fracture were older age, female sex, lower BMI, peripheral sensory neuropathy, and estimated glomerular filtration rate <45 mL/min/1.73 m2. The model-predicted mean 10-year incident fracture risk was 3.3% with good discrimination, calibration, and accuracy. For a 3% cutoff, sensitivity was 76.0%, specificity 71.9%, positive predictive value (PPV) 10.1%, and negative predictive value (NPV) 98.6%. Model performance in the small BHS sample was also good (sensitivity 66.7%, specificity 79.8%, PPV 6.2%, and NPV 99.2%). QFracture performed well in FDS1 but required availability of 25 variables. CONCLUSIONS: The FDS1 hip fracture risk equation is a simple validated adjunct to type 2 diabetes management that uses variables that are readily available in routine care.

Incidence and Determinants of Intraocular Lens Implantation in Type 2 Diabetes: The Fremantle Diabetes Study Phase II.

OBJECTIVE: To compare the incidence of intraocular lens (IOL) implantation for cataracts between people with and without type 2 diabetes and to determine associated risk factors in those with type 2 diabetes. RESEARCH DESIGN AND METHODS: Participants with type 2 diabetes (n = 1,499) from the community-based observational Fremantle Diabetes Study Phase II (FDS2) were age, sex, and zip code matched 1:4 with residents without diabetes. IOL implantation status was ascertained between entry (2008-2011) and the end of 2016 using validated data linkage. Age-specific incidence rates and incidence rate ratios (IRRs) for cataract surgery were calculated. Predictors of IOL implantation in FDS2 participants were assessed using proportional hazards and competing risk regression modeling. RESULTS: The crude IRR (95% CI) for cataract surgery in FDS2 participants (mean ± SD age 62.8 ± 10.8 years at entry) versus the matched group without diabetes was 1.50 (1.32-1.71), with the highest relative risk in those aged 45-54 years at the time of surgery (7.12 [2.05-27.66]). Competing risk analysis showed that age at entry, diabetes duration, serum HDL cholesterol, serum triglycerides, a severe hypoglycemic episode in the past year, and Asian and southern European ethnicity increased the risk of cataract surgery in participants with type 2 diabetes (P ≤ 0.025). CONCLUSIONS: People with type 2 diabetes, especially those in younger age-groups, are at a significantly increased risk of cataract surgery than matched people without diabetes. Multifaceted prevention strategies should be incorporated as part of routine care. As well as limiting ultraviolet light exposure, these might include lipid-modifying treatment and strategies to avoid severe hypoglycemia.

Glycaemic control and mortality in older people with type 2 diabetes: The Fremantle Diabetes Study Phase II.

AIM: To investigate whether tight glycaemic control achieved with metformin, insulin or sulphonylurea-based pharmacotherapy increases all-cause mortality in older people with type 2 diabetes. MATERIALS AND METHODS: We conducted a prospective cohort study of individuals with known diabetes recruited between 2008 and 2011 and followed until 2016. The impact of baseline glycated haemoglobin (HbA1c) on mortality hazards was investigated in participants aged ≥75 years. Proportional hazards models for time to death were constructed from the baseline clinical assessment, then the variables of interest (HbA1c, treatment category and their interactions) were entered. RESULTS: There were 367 participants (mean age 80.1 ± 3.9 years, median [interquartile range] HbA1c 50 [45-56] mmol/mol or 6.7 [6.3-7.3]%) who were followed for a median (interquartile range) 6.7 (4.5-7.7) years, during which 40.9% of the participants died. At baseline, 60.4% were on metformin-based treatment, 35.3% on sulphonylurea-based treatment and 23.2% on treatment including insulin. Baseline HbA1c was significantly associated with mortality in a model that included interactions between HbA1c and the three treatment-based groups compared with non-pharmacological treatment. The metformin treatment group had higher mortality when HbA1c levels were <48 mmol/mol (<6.5%) and the sulphonylurea and insulin treatment groups had higher mortality when HbA1c levels were <52 mmol/mol (<7.0%), with hazard ratios of 2.63 (95% confidence interval [CI] 1.39-4.97), 2.49 (95% CI 1.14-5.44) and 2.22 (95% CI 1.12-4.43), respectively. CONCLUSIONS: Tight glycaemic control may be hazardous in older people with type 2 diabetes when achieved with pharmacotherapy with metformin, and especially with insulin or sulphonylureas. These data confirm that overtreatment is likely to be an important clinical problem in this vulnerable population.

The relationship between circulating adiponectin, ADIPOQ variants and incident cardiovascular disease in type 2 diabetes: The Fremantle Diabetes Study.

AIMS: To investigate the relationship between serum adiponectin, ADIPOQ variants and haplotypes, and cardiovascular disease (CVD) in type 2 diabetes (T2D). METHODS: Baseline data including serum total adiponectin and 21 ADIPOQ polymorphisms were available for 1076 participants (mean age 64.0 years, 49.4% males) in a community-based cohort followed for an average of 12 years. RESULTS: During 8843 patient-years of follow-up for coronary heart disease (CHD), 13,494 patient-years for ischaemic stroke (IS) and 12,028 patient-years for heart failure (HF), 40.4%, 11.8% and 31.9% of patients experienced a first episode of CHD, IS or HF, respectively. In Cox regression after adjustment for the most parsimonious models, loge(serum adiponectin) and the ADIPOQ variant rs12495941 were inversely associated with incident CHD (hazard ratio [95% confidence interval] 0.79 [0.65-0.98] and 0.64 [0.44-0.94], respectively), while rs1648707 was positively associated with incident IS (2.05 [1.37-3.06]; all P ≤ 0.028). In males, rs9860747 and rs17366568 predicted CHD (0.22 [0.05-0.92] and 1.50 [1.01-2.20]; P ≤ 0.042), while rs1648707 and rs1063537 predicted IS (2.36 [1.32-4.23] and 2.09 [1.17-3.72]; P ≤ 0.012). In females, rs10937273 predicted CHD via an interaction with serum adiponectin (0.43 [0.21-0.91]; P = 0.027), while rs864265 predicted IS (0.43 [0.21-0.88], P = 0.021). The associations between ADIPOQ variants and outcomes were supported by haplotype block analysis. Neither serum adiponectin nor ADIPOQ variants predicted HF. CONCLUSIONS: Serum total adiponectin and gender-specific ADIPOQ variants predict CHD and IS, but not HF, independently of other risk factors in community-based patients with T2D. In contrast to some previous studies, there was no relationship between a high serum total adiponectin and CVD.

The relationship between intensification of blood glucose-lowering therapies, health status and quality of life in type 2 diabetes: The Fremantle Diabetes Study Phase II.

AIMS: To determine whether therapeutic intensification in type 2 diabetes influences health status and quality of life (QoL). METHODS: We studied 930 participants in the longitudinal observational Fremantle Diabetes Study Phase II (mean age 65.3 years, 53.8% males, median diabetes duration 8.0 years) with valid data from baseline assessment and two biennial reviews (4 years of follow-up) between 2008 and 2015. The main outcome measures were the Short Form-12 version 2 physical and mental health composite scores (PCS, MCS) and the average weighted impact (AWI) score from the Audit of Diabetes Dependent QoL. RESULTS: There were reductions in PCS at Year 4 compared with baseline and Year 2 in patients on stable diet-based management (n = 160), oral glucose-lowering medication (OGLM; n = 387), and insulin with/without OGLM (n = 168; P < 0.05), but no statistically significant temporal changes in MCS/AWI. Insulin-treated patients had the lowest PCS, MCS and AWI compared to the other two subgroups at each time-point (P ≤ 0.012). In participants initiating OGLM (n = 84) or insulin (n = 85), there were no differences in PCS, MCS or AWI at the biennial assessments either side of these therapeutic changes (P ≥ 0.08). CONCLUSIONS: These real-life data show that treatment intensification, including insulin initiation, does not impact adversely on patient well-being in community-based type 2 diabetes. Since insulin use at entry was associated with longer diabetes duration, worse glycaemic control, and a greater risk of chronic complications, the burden of disease rather than treatment modality appears the primary determinant of health status and QoL.

The utility of the Diabetes Anxiety Depression Scale in Type 2 diabetes mellitus: The Fremantle Diabetes Study Phase II.

BACKGROUND: Previous research using latent class analysis (LCA) identified classes of people with type 2 diabetes and specific profiles of depression and anxiety. Since LCA-derived anxious depression strongly predicts cardiovascular outcomes and mortality but cannot be applied to individuals, we developed a validated combined depression-anxiety metric, the Diabetes Anxiety Depression Scale (DADS), for potential clinical application in people with type 2 diabetes. METHODS: 1,337 participants with type 2 diabetes from the observational community-based Fremantle Diabetes Study Phase II completed the Patient Health Questionnaire 9-item version (PHQ-9) to assess symptoms of depression, and the Generalised Anxiety Disorder Scale (GADS) to assess symptoms of anxiety. A single score was calculated by adding all the PHQ-9 items and the four GADS items used for the LCA. Cut-off scores were calculated with Receiver Operating Characteristic (ROC) area under the curve (AUC). RESULTS: The optimum cut-off scores in terms of sensitivity, specificity, positive and negative predictive value were 18 points for major anxious depression and 8 points for minor anxious depression. A score of 8-17 was associated with a significantly increased incidence of coronary heart disease, whereas a score 18-39 was associated with an increase in both coronary heart disease and cardiovascular mortality. CONCLUSIONS: The DADS has strong psychometric validity in the identification of mixed depression-anxiety in type 2 diabetes, and may contribute to cardiovascular risk prediction.