Prevalence and prognostic significance of cardiac autonomic neuropathy in community-based people with type 2 diabetes: the Fremantle Diabetes Study Phase II.

BACKGROUND: There is a paucity of contemporary data on the prevalence and prognostic significance of cardiac autonomic neuropathy (CAN) from community-based cohorts with type 2 diabetes assessed using gold standard methods. The aim of this study was to assess these aspects of CAN in the longitudinal observational Fremantle Diabetes Study Phase II (FDS2). METHODS: FDS2 participants were screened at baseline using standardised cardiovascular reflex tests (CARTs) of heart rate variation during deep breathing, Valsalva manoeuvre and standing. CAN (no/possible/definite) was assessed from the number of abnormal CARTs. Multinomial regression identified independent associates of CAN status. Cox proportional hazards modelling determined independent baseline predictors of incident heart failure (HF) and ischaemic heart disease (IHD), and all-cause mortality. RESULTS: Of 1254 participants assessed for CAN, 86 (6.9%) were outside CART age reference ranges and valid CART data were unavailable for 338 (27.0%). Of the remaining 830 (mean age 62.3 years, 55.3% males, median diabetes duration 7.3 years), 51.0%, 33.7% and 15.3% had no, possible or definite CAN, respectively. Independent associates of definite CAN (longer diabetes duration, higher body mass index and resting pulse rate, antidepressant and antihypertensive therapies, albuminuria, distal sensory polyneuropathy, prior HF) were consistent with those reported previously. In Kaplan-Meier analysis, definite CAN was associated with a lower likelihood of incident IHD and HF versus no/possible CAN (P < 0.001) and there was a graded increase in all-cause mortality risk from no CAN to possible and definite CAN (P < 0.001). When CAN category was added to the most parsimonious models, it was not a significant independent predictor of IHD (P ≥ 0.851) or HF (P ≥ 0.342). Possible CAN (hazard ratio (95% CI) 1.47 (1.01, 2.14), P = 0.046) and definite CAN (2.42 (1.60, 3.67), P < 0.001) increased the risk of all-cause mortality versus no CAN. CONCLUSIONS: Routine screening for CAN in type 2 diabetes has limited clinical but some prognostic value.

Pulmonary Function Trajectories Over 6 Years and Their Determinants in Type 2 Diabetes: The Fremantle Diabetes Study Phase II.

OBJECTIVE: To assess whether there are clusters of people with type 2 diabetes with distinct temporal profiles of lung function changes and characteristics. RESEARCH DESIGN AND METHODS: Group-based trajectory modeling (GBTM) identified groups of participants with type 2 diabetes from the community-based observational Fremantle Diabetes Study Phase II (FDS2) who had at least two biennial measurements of forced expiratory volume in 1 s as a percentage of predicted (FEV1%pred) over 6 years. Independent associates of group membership were assessed using multinomial regression. RESULTS: Of 1,482 potential FDS2 participants, 1,074 (72.5%; mean age, 65.2 years; 45.5% female; median diabetes duration, 8.0 years) were included in the modeling. The best fitting GBTM model identified four groups categorized by FEV1%pred trajectory: high (19.5%; baseline FEV1%pred, 106.5 ± 9.5%; slope 0%/year), medium (47.7%; FEV1%pred, 87.3 ± 8.7%; slope, -0.32%/year), low (25.0%; baseline FEV1%pred, 68.9 ± 9.8%; slope, -0.72%/year), and very low (7.9%; baseline FEV1%pred, 48.8 ± 9.6%; slope, -0.68%/year). Compared with the high group, the other groups were characterized by nonmodifiable and modifiable risk factors associated with lung function decline in the general population (including ethnicity, marital status, smoking, obesity, coronary heart disease, and chronic respiratory disease). The main, diabetes-specific, significant predictor of group membership was a higher HbA1c in the very low group. There was a graded increase in mortality from 6.7% in the high group to 22.4% in the very low group. CONCLUSIONS: Measurement of lung function in type 2 diabetes could help optimize clinical management and improve prognosis, including addressing glycemic control in those with a very low FEV1%pred.

Serum vitamin B12, distal symmetrical polyneuropathy and anaemia in type 2 diabetes: the Fremantle Diabetes Study Phase 2.

BACKGROUND: There are limited data relating to the effects of metformin-associated vitamin B12 deficiency on the risk of distal symmetrical polyneuropathy (DSPN) and megaloblastic anaemia in well-characterised community-based cohorts. AIMS: To assess inter-relationships between metformin therapy, vitamin B12 deficiency assessed using serum active B12 concentrations, and DSPN and anaemia in 1492 Fremantle Diabetes Study Phase 2 (FDS2) participants with type 2 diabetes. METHODS: Prevalence rates of vitamin B12 deficiency (total <80 pmol/L, active <23 pmol/L) and borderline deficiency (total ≥80 and ≤200 pmol/L, active ≥23 and ≤35 pmol/L) were determined using baseline sera. The relationship between vitamin B12 status and both DSPN and anaemia was assessed using multivariable analyses. RESULTS: Most FDS2 participants (94.4%) were vitamin B12 replete (total serum concentration >200 pmol/L, active >35 pmol/L), 2.0% were deficient (total <80 pmol/L, active <23 pmol/L) and the remainder (3.6%) borderline. Although metformin treatment increased the odds of deficiency (4.2%, 3.1% borderline) in a dose-dependent fashion (odds ratio (95% confidence interval) 39.4 (4.90-316) for >2000 mg daily compared with no treatment; P < 0.001), there was no significant association between vitamin B12 status and DSPN, anaemia (haemoglobin ≤130 g/L males, ≤120 g/L females), haemoglobin concentration or mean corpuscular volume (P ≥ 0.147). Metformin increased the likelihood of anaemia, especially at high doses, independent of vitamin B12 deficiency. CONCLUSIONS: Since nutritional sources likely attenuate metformin-associated vitamin B12 malabsorption and its clinical sequelae in developed countries such as Australia, there is no need for routine/opportunistic serum vitamin B12 screening in metformin-treated patients.

Temporal Trends in Distal Symmetric Polyneuropathy in Type 2 Diabetes: The Fremantle Diabetes Study.

CONTEXT: Macrovascular outcomes in type 2 diabetes have improved over recent decades. There are scant equivalent distal symmetric polyneuropathy (DSPN) data. OBJECTIVE: This work aimed to characterize temporal changes in DSPN prevalence and incidence rates (IRs) in community-based Australians. METHODS: An observational study was conducted among an urban population. Participants included individuals with type 2 diabetes from the Fremantle Diabetes Study phases I (FDS1; n = 1296 recruited 1993-1996) and II (FDS2; n = 1509 recruited 2008-2011). Main outcome measures included Michigan Neuropathy Screening Instrument (MNSI) clinical grading. RESULTS: DSPN prevalence by 8-point MNSI was 30.8% (FDS1) and 58.9% (FDS2; P < .001), and by 6-point (excluding foot appearance) and 2-point (biothesiometry alone) MNSI was 37.5% and 35.7% (P = .336), and 33.8% and 38.7% (P = .011), respectively. Given between-phase changes in appearance assessment, 8-point MNSI data were not analyzed further. In multivariable analysis, FDS2 vs FDS1 participation was associated with 6-point (odds ratio (95% CI) 0.68 (0.56-0.83); P < .001) but not 2-point (0.90 (0.74-1.11); P = .326) MNSI DSPN prevalence. Four-year DSPN IRs (95% CI) for 6-point MNSI were 13.6 (12.0-15.4) and 17.6 (15.9-19.4)/100 person-years in FDS1 and FDS2, respectively (IR ratio [IRR] 1.31 [1.12-1.55]; P < .001), and for 2-point MNSI were 13.9 (12.3-15.8) and 7.4 (16.3-8.6/100 person-years; IRR 0.53 [0.43-0.64]; P < .001). FDS2 vs FDS1 independently predicted incident DSPN for 6-point (hazard ratio [95% CI] 1.25 [1.06-1.48]; P = .009) and 2-point (0.42 [0.33-0.55]; P < .001) MNSI. CONCLUSION: DSPN prevalence was lower or equivalent in FDS2 vs FDS1, and its incidence was greater or lower, in multivariable models depending on the MNSI features used.

The Relationship between Pulmonary Artery Pressure and Mortality in Type 2 Diabetes: A Fremantle Diabetes Study Phase II and National Echocardiographic Database of Australia Data Linkage Study.

An elevated estimated right ventricular systolic pressure (eRVSP) identified on echocardiography is present in one-third of individuals with type 2 diabetes, but its prognostic significance is unknown. To assess the relationship between eRVSP and mortality, prospective data from 1732 participants in the Fremantle Diabetes Study Phase II were linked with the National Echocardiographic Database of Australia. Of this cohort, 416 (mean age 70.6 years, 47.4% males) had an eRVSP measured and 381 (91.4%) had previously confirmed type 2 diabetes. Receiver- operating characteristic analysis of the relationship between eRVSP and all-cause mortality was conducted. Survival analyses were performed for participants with type 2 diabetes diagnosed before first measured eRVSP (n = 349). Cox regression identified clinical and echocardiographic associates of all-cause mortality. There were 141 deaths (40.4%) during 2348 person-years (mean ± SD 6.7 ± 4.0 years) of follow-up. In unadjusted Kaplan-Meier analysis, mortality rose with higher eRVSP (log-rank test, p < 0.001). In unadjusted pairwise comparisons, eRVSP >30 to 35, >35 to 40, and >40 mmHg had significantly increased mortality compared with eRVSP ≤ 30 mmHg (p = 0.025, p = 0.001, p < 0.001, respectively). There were 50 deaths in 173 individuals (29.1%) with eRVSP ≤ 30 mmHg, and 91 in 177 (51.4%) with eRVSP > 30 mmHg (log-rank test, p < 0.001). In adjusted models including age, Aboriginal descent, Charlson Comorbidity Index ≥ 3 and left heart disease, eRVSP > 30 mmHg predicted a two-fold higher all-cause mortality versus ≤ 30 mmHg. An eRVSP > 30 mmHg predicts increased all-cause mortality in type 2 diabetes. Where available, eRVSP could inform type 2 diabetes outcome models.

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.

Temporal trends in chronic complications of diabetes by sex in community-based people with type 2 diabetes: the Fremantle Diabetes Study.

BACKGROUND: Whether recent reductions in cardiovascular disease (CVD) events and mortality in type 2 diabetes apply equally to both sexes is largely unknown. The aim of this study was to characterize temporal changes in CVD events and related outcomes in community-based male and female Australian adults with type 2 diabetes or without known diabetes. METHODS: Participants from the longitudinal observational Fremantle Diabetes Study Phases I (FDS1; n = 1291 recruited 1993-1996) and II (FDS2; n = 1509 recruited 2008-2011) and four age-, sex- and postcode-matched individuals without diabetes (FDS1 n = 5159; FDS2 n = 6036) were followed for first myocardial infarction, stroke, heart failure hospitalization, lower extremity amputation, CVD death and all-cause mortality. Five-year incidence rates (IRs) for males versus females in FDS1 and FDS2 were calculated, and IR ratios (IRRs) derived. RESULTS: The FD1 and FDS2 participants were of mean age 64.0 and 65.4 years, respectively, and 48.7% and 51.8% were males. For type 2 diabetes, IRRs for all endpoints were 11-62% lower in FDS2 than FDS1 for both sexes. For participants without diabetes, IRRs were 8-56% lower in FDS2 versus FDS1 apart from stroke in females (non-significantly 41% higher). IRRs for males versus females across FDS phases were not significantly different for participants with type 2 diabetes or those without diabetes (P-values for male * FDS2 interaction ≥ 0.0.083 adjusted for age). For risk factors in participants with type 2 diabetes, greater improvements between FDS1 and FDS2 in smoking rates in males were offset by a greater reduction in systolic blood pressure in females. CONCLUSIONS: The incidence of chronic complications in Australians with type 2 diabetes and without diabetes has fallen similarly in both sexes over recent decades, consistent with comparably improved overall CVD risk factor management.

Comparative mortality and its determinants in community-based people with type 1 diabetes: the Fremantle Diabetes Study Phase I.

INTRODUCTION: The aim of this study was to compare mortality in community-based Australians with type 1 diabetes (T1D), without diabetes, or with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: The longitudinal observational Fremantle Diabetes Study Phase I (FDS1) T1D cohort, matched people without diabetes from the FDS1 catchment area, and matched FDS1 participants with T2D were followed up from entry (1993-1996) to death/end-2017. Mortality rates (MRs) and mortality rate ratios (MRRs) were calculated. Cox regression models identified independent determinants of death. RESULTS: Of 121 participants with T1D and 484 age/sex/postcode-matched people without diabetes (pooled mean±SD age 43.1±15.3 years, 59.2% men), 55 (45.5%, MR 25.7 (95% CI 19.4 to 33.5)/1000 person-years) and 88 (18.2%, MR 8.5 (95% CI 6.8 to 10.4)/1000 person-years), respectively, died during 12 541 person-years of follow-up (MRR 3.04 (95% CI 2.13 to 4.31), p<0.001). Among participants with T1D, diagnosis at age 18-27 years and baseline HbA1c, urinary albumin:creatinine ratio, and retinopathy were independent predictors of death (p≤0.011). Twenty-five FDS1 participants died from cardiovascular disease (MR 11.7 (95% CI 7.6 to 17.3)/1000 person-years) vs 28 residents without diabetes (MR 2.7 (95% CI 1.8 to 3.9)/1000 person-years; MRR (95% CI) 4.34 (2.43, 7.73) (p<0.001). There were 93 FDS1 participants with T1D who were age/sex matched with an FDS1 participant with T2D and 53 (57.0%) and 37 (39.8%), respectively, died (p=0.027). In pooled Cox regression analysis, T1D was not a determinant of mortality (HR 1.18 (95% CI 0.71 to 1.97), p=0.523). CONCLUSIONS: T1D substantially increases the risk of death, especially when diagnosed in late adolescence/young adulthood. Diabetes type does not influence mortality after adjustment for key confounding variables.

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.

Serum bicarbonate concentration and the risk of death in type 2 diabetes: the Fremantle Diabetes Study Phase II.

AIMS: To examine whether all-cause mortality is independently associated with serum bicarbonate concentration below the laboratory reference interval in a representative, well-characterised community-based cohort of people with type 2 diabetes. METHODS: 1478 FDS2 participants with type 2 diabetes (mean age 65.8 years, 51.6% males, median diabetes duration 9.0 years) from the longitudinal, observational Fremantle Diabetes Study Phase II (FDS2) were followed from study entry to death or end-2016. Independent associates of a low baseline serum bicarbonate (< 22 mmol/L) were determined using multiple logistic regression. The role of important covariates in influencing the association between bicarbonate and mortality was assessed by a stepwise Cox regression approach. RESULTS: A low serum bicarbonate was associated with increased all-cause mortality in unadjusted analysis (hazard ratio (HR) 1.90 (95% confidence limits (CL) 1.39, 2.60 per mmol/L). Mortality remained significantly associated with low serum bicarbonate (HR 1.40 (95% CL 1.01, 1.94) per mmol/L) in a Cox regression model with adjustment for factors associated with mortality but not low serum bicarbonate, but inclusion of estimated glomerular filtration rate categories rendered the association non-significant (HR 1.16 (95% CL 0.83, 1.63) per mmol/L). CONCLUSIONS: A low serum bicarbonate is not an independent prognostic marker in people with type 2 diabetes but it may be a manifestation of the pathway between the development of impaired renal function and death.

Temporal trends in minor and major lower extremity amputation in people with type 2 diabetes: The Fremantle Diabetes Study.

AIMS: To determine whether incident minor and major lower extremity amputations (LEAs) have declined in recent decades in type 2 diabetes. METHODS: Participants with type 2 diabetes from the community-based Fremantle Diabetes Study Phases I (FDS1; n = 1,296, mean age 64.0 years, recruited 1993-1996) and II (FDS2; n = 1,509, mean age 65.4 years, recruited 2008-2011) were followed from entry to incident minor/major LEA, death or five years. Cox regression determined hazard ratios (HRs) for each outcome for FDS2 versus FDS1 and independent predictors of incident minor and major LEA in the combined cohort. RESULTS: Age- and sex-adjusted HRs (95% CIs) in FDS2 versus FDS1 for incident minor and major LEA were, respectively, 0.60 (0.27, 1.35) and 0.59 (0.22, 1.59). Higher glycated haemoglobin, urine albumin: creatinine (uACR) ratio and peripheral sensory neuropathy (PSN) were independent predictors of incident minor LEA. Higher fasting serum glucose, peripheral arterial disease (PAD), end-stage kidney disease and prior diabetes-related minor LEA were associated with incident major LEA. CONCLUSIONS: There were non-significant reductions of approximately 40% in incident minor and major LEA in community-based people with type 2 diabetes during the 15 years between FDS Phases. Predictors of minor/major LEA confirm distinct high-risk patient groups with implications for clinical management.

Retinopathy prevalence, incidence and trajectories in type 2 diabetes: The Fremantle diabetes study phase II.

AIMS: To determine diabetic retinopathy (DR) prevalence, incidence, and whether distinct trajectories are associated with DR-complicating Type 2 diabetes. METHODS: Retinal photographs from Fremantle Diabetes Study Phase II (FDS2) participants with Type 2 diabetes recruited in 2008-2011 and who attended biennial assessments for up to 6 years were graded as no DR, mild non-proliferative DR (NPDR), moderate NPDR or severe NPDR/proliferative DR. Baseline DR prevalence, and the cumulative incidence of moderate NPDR or worse in those without DR at baseline, were calculated. Group-based DR trajectory modelling was performed. Logistic regression determined independent associates of incident moderate NPDR or worse and trajectory group membership. RESULTS: Of 1521 participants (mean age 65.6 years, 52.1% males, median diabetes duration 9.0 years; 98% of all FDS2 participants with Type 2 diabetes) with gradable baseline photographs, 563 (37.0%) had DR. During a median 6.1 years of follow-up, 23 (3.2%) without baseline DR developed at least moderate NPDR (crude incidence 6.1/1000 person-years) with HbA1c the sole independent predictor (odds ratio [95% CI]: 1.62 [1.30-2.02] per 1% [11 mmol/mol] increase). Trajectory analysis showed two distinct groups, those with baseline/persistent DR (20%) and those remaining DR free (80%). Longer diabetes duration, insulin use, higher mean HbA1c , higher mean systolic blood pressure and higher mean urinary albumin: creatinine ratio all increased the odds (p ≤ 0.014) of being in the persistent DR trajectory group. CONCLUSIONS: The low incidence of at least moderate NPDR reflects the trajectory analysis. The currently recommended biennial retinal screening frequency for individuals without DR could potentially be extended.

A survey of simian Plasmodium infections in humans in West Kalimantan, Indonesia.

The simian parasite Plasmodium knowlesi is the predominant species causing human malaria infection, including hospitalisations for severe disease and death, in Malaysian Borneo. By contrast, there have been only a few case reports of knowlesi malaria from Indonesian Borneo. This situation seems paradoxical since both regions share the same natural macaque hosts and Anopheles mosquito vectors, and therefore have a similar epidemiologically estimated risk of infection. To determine whether there is a true cross-border disparity in P. knowlesi prevalence, we conducted a community-based malaria screening study using PCR in Kapuas Hulu District, West Kalimantan. Blood samples were taken between April and September 2019 from 1000 people aged 6 months to 85 years attending health care facilities at 27 study sites within or close to jungle areas. There were 16 Plasmodium positive samples by PCR, five human malarias (two Plasmodium vivax, two Plasmodium ovale and one Plasmodium malariae) and 11 in which no species could be definitively identified. These data suggest that, if present, simian malarias including P. knowlesi are rare in the Kapuas Hulu District of West Kalimantan, Indonesian Borneo compared to geographically adjacent areas of Malaysian Borneo. The reason for this discrepancy, if confirmed in other epidemiologically similar regions of Indonesian Borneo, warrants further studies targeting possible cross-border differences in human activities in forested areas, together with more detailed surveys to complement the limited data relating to monkey hosts and Anopheles mosquito vectors in Indonesian Borneo.

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.

The relationship between pancreatic cancer and type 2 diabetes: the Fremantle Diabetes Study Phase I.

Pancreatic cancer incidence was double (incidence rate ratio 2.06) in community-based adults with (n = 1291) versus without (n = 5158) type 2 diabetes followed for up to 25 years in the Fremantle Diabetes Study Phase 1. Sustained higher fasting plasma glucose reflecting insulin resistance and fewer comorbidities were statistically significant risk factors in the cohort with diabetes. Past pancreatitis was an aetiologically significant determinant in the cohort as a whole.

Temporal Trends in Renal Replacement Therapy in Community-Based People with or without Type 2 Diabetes: The Fremantle Diabetes Study.

BACKGROUND: Although rates of cardiovascular disease complicating type 2 diabetes are declining, equivalent data for renal replacement therapy (RRT) are conflicting. The aim of this study was to characterize temporal changes in RRT incidence rates (IRs) in Australians with or without type 2 diabetes. METHODS: Participants with type 2 diabetes from the Fremantle Diabetes Study Phases I (FDS1; n = 1291 recruited 1993-1996) and II (FDS2; n = 1509 recruited 2008-2011) were age-, sex- and postcode-matched 1:4 to people without diabetes and followed for first hospitalization for/with RRT. Five-year IRs, IR ratios (IRRs) for those with versus without diabetes in FDS1 and FDS2, and IR differences (IRDs), were calculated. RESULTS: The 13,995 participants had a mean age of 64.8 years and 50.4% were males. For the type 2 diabetes cohorts, the 5-year RRT IR was nearly threefold higher in FDS2 versus FDS1 (IRR (95% CI): 2.85 (1.01-9.87)). Sixteen more participants with type 2 diabetes/10,000 person-years received RRT in FDS2 than FDS1 compared with an IRD of 2/10,000 person-years in those without diabetes. Type 2 diabetes increased RRT risk at least 5-fold. This increased risk was greater in Aboriginal participants who were relatively young when RRT was initiated and more prone to rapid progression to RRT. Multivariable analysis using the combined FDS type 2 diabetes cohorts confirmed albuminuria as a strong independent RRT risk factor. CONCLUSIONS: The incidence of RRT is increasing substantially in Australians with type 2 diabetes, especially in Aboriginals who progress to RRT more rapidly at a younger age than non-Aboriginals.

Differences in retinopathy prevalence and progression between Anglo-Celt and Aboriginal Australians: the Fremantle Diabetes Study Phase II.

BACKGROUND: Indigenous populations have higher rates of diabetes and diabetic complications, yet there is a paucity of contemporary data on diabetic retinopathy (DR) prevalence and incidence in urban dwelling Aboriginal Australians. AIMS: The aim of the study was to compare the prevalence of DR and incidence of new or worsening DR between Aboriginal Australians and Anglo-Celts with Type 2 diabetes. METHODS: Participants from the community-based Fremantle Diabetes Study Phase II (817 Anglo-Celts, 94 Aboriginal people) recruited between 2008 and 2011 underwent fundus photography at baseline and biennial reviews. The prevalence of any DR and moderate non-proliferative DR (NPDR), and the incidence of new or worsening DR were ascertained using baseline and 4-year follow-up data. RESULTS: Compared with Anglo-Celts, the Aboriginal participants had a higher prevalence of any DR (33.0% vs 52.1%) and moderate NPDR or worse (5.1% vs 24.4%), and new or worsening DR during follow up (6.7% vs 23.5%). The unadjusted odds ratios (95% confidence interval) of any DR and moderate NPDR at baseline were 2.21 (1.43, 3.39) and 5.98 (3.40, 10.50), respectively, and of new or worsening DR 4.32 (1.33, 13.98). In adjusted models, Aboriginal ethnicity was only associated with the prevalence of moderate NPDR or worse (5.58 (2.44, 12.76)). CONCLUSIONS: Aboriginal participants had a higher prevalence of DR and new or worsening DR, reflecting conventional risk factors including suboptimal glycaemic control. Their significantly higher odds of moderate NPDR or worse in adjusted models suggest ethnic-specific determinants of DR severity. These findings highlight the need for equitable, culturally appropriate diabetes/ophthalmic care.

The pharmacokinetic properties of artemether and lumefantrine in Malaysian patients with Plasmodium knowlesi malaria.

AIMS: The aim of this study was to assess the pharmacokinetic properties of artemether, lumefantrine and their active metabolites in Plasmodium knowlesi malaria. METHODS: Malaysian adults presenting with uncomplicated P. knowlesi infections received six doses of artemether (1.7 mg/kg) plus lumefantrine (10 mg/kg) over 3 days. Venous blood and dried blood spot (DBS) samples were taken at predetermined time-points over 28 days. Plasma and DBS artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine were measured using liquid chromatography-mass spectrometry. Multi-compartmental population pharmacokinetic models were developed using plasma with or without DBS drug concentrations. RESULTS: Forty-one participants (mean age 45 years, 66% males) were recruited. Artemether-lumefantrine treatment was well tolerated and parasite clearance was prompt. Plasma and DBS lumefantrine concentrations were in close agreement and were used together in pharmacokinetic modelling, but only plasma concentrations of the other analytes were used because of poor correlation with DBS levels. The areas under the concentration-time curve (AUC0-∞ ) for artemether, dihydroartemisinin and lumefantrine (medians 1626, 1881 and 625 098 µg.h/L, respectively) were similar to those reported in previous pharmacokinetic studies in adults and children. There was evidence of auto-induction of artemether metabolism (mean increase in clearance relative to bioavailability 25.2% for each subsequent dose). The lumefantrine terminal elimination half-life (median 9.5 days) was longer than reported in healthy volunteers and adults with falciparum malaria. CONCLUSION: The disposition of artemether, dihydroartemisinin and lumefantrine in knowlesi malaria largely parallels that in other human malarias. DBS lumefantrine concentrations can be used in pharmacokinetic studies but DBS technology is currently unreliable for the other analytes.