Urine Albumin-Creatinine Ratio Variability in People With Type 2 Diabetes: Clinical and Research Implications.

RATIONALE & OBJECTIVE: Evidence has demonstrated that albuminuria is a key diagnostic and prognostic marker of diabetic chronic kidney disease, but the impact of its day-to-day variability has not been adequately considered. This study quantified within-individual variability of albuminuria in people with type 2 diabetes to inform clinical albuminuria monitoring. STUDY DESIGN: Descriptive cross-sectional analysis. SETTING & PARTICIPANTS: People with type 2 diabetes (n=826, 67.1 [IQR, 60.3-72.4] years, 64.9% male) participating in the Progression of Diabetic Complications (PREDICT) cohort study. EXPOSURE: Four spot urine collections for measurement of urinary albumin-creatinine ratio (UACR) within 4 weeks. OUTCOME: Variability of UACR. ANALYTICAL APPROACH: We characterized within-individual variability (coefficient of variation [CV], 95% limits of random variation, intraclass correlation coefficient), developed a calculator displaying probabilities that any observed difference between a pair of UACR values truly exceeded a 30% difference, and estimated the ranges of diagnostic uncertainty to inform a need for additional UACR collections to exclude or confirm albuminuria. Multiple linear regression examined factors influencing UACR variability. RESULTS: We observed high within-individual variability (CV 48.8%; 95% limits of random variation showed a repeated UACR to be as high/low as 3.78/0.26 times the first). If a single-collection UACR increased from 2 to 5mg/mmol, the probability that UACR actually increased by at least 30% was only 50%, rising to 97% when 2 collections were obtained at each time point. The ranges of diagnostic uncertainty were 2.0-4.0mg/mmol after an initial UACR test, narrowing to 2.4-3.2 and 2.7-2.9mg/mmol for the mean of 2 and 3 collections, respectively. Some factors correlated with higher (female sex; moderately increased albuminuria) or lower (reduced estimated glomerular filtration rate and sodium-glucose cotransporter 2 inhibitor/angiotensin-converting enzyme inhibitor/angiotensin receptor blocker treatment) within-individual UACR variability. LIMITATIONS: Reliance on the mean of 4 UACR collections as the reference standard for albuminuria. CONCLUSIONS: UACR demonstrates a high degree of within-individual variability among individuals with type 2 diabetes. Multiple urine collections for UACR may improve capacity to monitor changes over time in clinical and research settings but may not be necessary for the diagnosis of albuminuria. PLAIN-LANGUAGE SUMMARY: Albuminuria (albumin in urine) is a diagnostic and prognostic marker of diabetic chronic kidney disease. However, albuminuria can vary within an individual from day to day. We compared 4 random spot urinary albumin-creatinine ratio (UACR) samples from 826 participants. We found that a second UACR collection may be as small as a fourth or as large as almost 4 times the first sample's UACR level. This high degree of variability presents a challenge to our ability to interpret changes in albuminuria. Multiple collections have been suggested as a solution. We have constructed tools that may aid clinicians in deciding how many urine collections are required to monitor and diagnose albuminuria. Multiple urine collections may be required for individual monitoring but not necessarily for diagnosis.

Evaluating the incidence of complications among people with diabetes according to age of onset: Findings from the UK Biobank.

AIMS: To examine the impact of current age, age at diagnosis, and duration of diabetes on the incidence rate of complications among people with type 2 diabetes. METHODS: Baseline data from 19,327 individuals with type 2 diabetes in the UK Biobank were analysed. Poisson regression was used to model incidence rates by current age, age at diagnosis, and duration of diabetes for the following outcomes: myocardial infarction (MI), heart failure (HF), stroke, end-stage kidney diseases (ESKD), chronic kidney diseases (CKD), liver diseases, depression, and anxiety. RESULTS: The mean age at baseline was 60.2 years, and median follow-up was 13.9 years. Diabetes duration was significantly longer among those with younger-onset type 2 diabetes (diagnosed at <40 years) compared to later-onset type 2 diabetes (diagnosed at ≥40 years), 16.2 and 5.3 years, respectively. Incidence rates of MI, HF, stroke, and CKD had strong positive associations with age and duration of diabetes, whereas incidence rates of ESKD liver diseases, and anxiety mainly depended on duration of diabetes. The incidence rates of depression showed minor variation by age and duration of diabetes and were highest among those diagnosed at earlier ages. No clear evidence of an effect of age of onset of diabetes on risk of complications was apparent after accounting for current age and duration of diabetes. CONCLUSIONS: Our study indicates age at diagnosis of diabetes does not significantly impact the incidence of complications, independently of the duration of diabetes. Instead, complications are primarily influenced by current age and diabetes duration.

Effect of a 3-Year Lifestyle Intervention in Patients with Chronic Kidney Disease: A Randomized Clinical Trial.

BACKGROUND: Supervised lifestyle interventions have the potential to significantly improve physical activity and fitness in patients with CKD. METHODS: To assess the efficacy of a lifestyle intervention in patients with CKD to improve cardiorespiratory fitness and exercise capacity over 36 months, we conducted a randomized clinical trial, enrolling 160 patients with stage 3-4 CKD, with 81 randomized to usual care and 79 to a 3-year lifestyle intervention. The lifestyle intervention comprised care from a multidisciplinary team, including a nephrologist, nurse practitioner, exercise physiologist, dietitian, diabetes educator, psychologist, and social worker. The exercise training component consisted of an 8-week individualized and supervised gym-based exercise intervention followed by 34 months of a predominantly home-based program. Self-reported physical activity (metabolic equivalent of tasks [METs] minutes per week), cardiorespiratory fitness (peak O2 consumption [VO2peak]), exercise capacity (maximum METs and 6-minute walk distance) and neuromuscular fitness (grip strength and get-up-and-go test time) were evaluated at 12, 24, and 36 months. RESULTS: The intervention increased the percentage of patients meeting physical activity guideline targets of 500 MET min/wk from 29% at baseline to 63% at 3 years. At 12 months, both VO2peak and METs increased significantly in the lifestyle intervention group by 9.7% and 30%, respectively, without change in the usual care group. Thereafter, VO2peak declined to near baseline levels, whereas METs remained elevated in the lifestyle intervention group at 24 and 36 months. After 3 years, the intervention had increased the 6-minute walk distance and blunted declines in the get-up-and-go test time. CONCLUSIONS: A 3-year lifestyle intervention doubled the percentage of CKD patients meeting physical activity guidelines, improved exercise capacity, and ameliorated losses in neuromuscular and cardiorespiratory fitness.

Association of biomarkers and risk scores with subclinical left ventricular dysfunction in patients with type 2 diabetes mellitus.

BACKGROUND: Subclinical LV dysfunction (LVD) identifies heart failure (HF) risk in type 2 diabetes mellitus (T2DM). We sought the extent to which clinical scores (ARIC-HF, WATCH-DM), natriuretic peptides (NTpBNP) and troponin (hs-TnT) were associated with subclinical LV dysfunction (LVD). These associations could inform the ability of these tests to identify which patients should undergo echocardiography. METHODS: Participants with T2DM were prospectively recruited from three community-based populations. ARIC-HF risk at 4 years and WATCH-DM scores were calculated from clinical data. NTpBNP and hs-TnT were measured using an electro-chemiluminescence assay. All underwent a comprehensive echocardiogram. We calculated the sensitivity and specificity of clinical scores and biomarkers to identify abnormal global longitudinal strain (GLS ≥ -16%)), diastolic function (E/e' ≥ 14 or e' < 8 cm/s), left atrial volume index (LAV > 34 ml/m2) and LV hypertrophy (LV mass index > 88 g/m2 (F) > 102 g/m2(M)). RESULTS: Of 804 participants (median age 69 years [inter-quartile range (IQR) 65-73], 36% female), clinical scores suggested significant HF risk (median ARIC-HF 8% [IQR 4-12]; WATCH-DM 10 points [IQR 8-12]), and the median NTpBNP was 50 pg/mL [IQR 25-101] and hs-TnT 9.6 pg/mL [IQR 6.8-13.6]. Abnormal GLS was present in 126 (17%), elevated E/e' in 114 (15%), impaired e' in 629 (78%), increased LAV in 351 (44%) and LV hypertrophy in 113 (14%). After adjustments for age, body-mass index, and renal function, each standard deviation increase in NTpBNP was associated with a GLS increase of 0.32 (p < 0.001) and hs-TnT increase by 0.26 (p < 0.001). Similar trends were observed with ARIC-HF (standardised ß = 0.22, p < 0.001) and WATCH-DM (standardised ß = 0.22, p < 0.001) in univariable analyses. However, none of the risk assessment tools provided satisfactory discrimination for abnormal GLS (AUC 63%), diastolic indices (e' AUC 54-61%) or LV mass (AUC 59-67%). At a sensitivity of 90%, there was an unacceptably low (< 50%) specificity. CONCLUSION: Although risk assessment based on clinical scores or biomarkers would be desirable to stratify HF risk in people with T2DM, they show a weak relationship with subclinical LVD.

Excess all-cause and cause-specific mortality for people with diabetes and end-stage kidney disease.

AIMS: Excess mortality is high in the setting of diabetes and end-stage kidney disease (ESKD), but the effects of ESKD beyond diabetes itself remains incompletely understood. We examined excess mortality in people with diabetes with versus without ESKD, and variation by age, sex and diabetes type. METHODS: This study included 63,599 people with type 1 (aged 20-69 years; 56% men) and 1,172,160 people with type 2 diabetes (aged 30+ years; 54% men), from the Australian National Diabetes Services Scheme. Initiation of renal replacement therapy and mortality outcomes were obtained via linkage to the Australia and New Zealand Dialysis and Transplant Registry and the National Death Index, respectively. Excess mortality was measured by calculating the mortality rate ratio (MRR) for people with versus without ESKD via indirect standardisation. RESULTS: A total of 9027 people developed ESKD during 8,601,522 person-years of follow-up. Among people with type 1 diabetes, the MRR was 34.9 (95%CI: 16.6-73.1) in men and 41.5 (20.8-83.1) in women aged 20-29 years and was 5.6 (4.5-7.0) and 7.4 (5.5-10.1) in men and women aged 60-69 years, respectively. In type 2 diabetes, MRRs were 16.6 (8.6-31.8) and 35.8 (17.0-75.2) at age 30-39 years and were 2.8 (2.6-3.1) and 3.6 (3.2-4.1) at age 80+ years in men and women, respectively. Excess cause-specific mortality was highest for peripheral artery disease, cardiac arrest, and infections, and lowest for cancer. CONCLUSIONS: Among people with diabetes, excess mortality in ESKD is much higher at younger ages and is higher for women compared with men.

Impact of the COVID-19 pandemic and lockdown restrictions on psychosocial and behavioural outcomes among Australian adults with type 2 diabetes: Findings from the PREDICT cohort study.

AIM: To examine psychosocial and behavioural impacts of the novel coronavirus disease 2019 (COVID-19) pandemic and lockdown restrictions among adults with type 2 diabetes. METHODS: Participants enrolled in the PRogrEssion of DIabetic ComplicaTions (PREDICT) cohort study in Melbourne, Australia (n = 489 with a baseline assessment pre-2020) were invited to complete a phone/online follow-up assessment in mid-2020 (i.e., amidst COVID-19 lockdown restrictions). Repeated assessments that were compared with pre-COVID-19 baseline levels included anxiety symptoms (7-item Generalised Anxiety Disorder scale [GAD-7]), depressive symptoms (8-item Patient Health Questionnaire [PHQ-8]), diabetes distress (Problem Areas in Diabetes scale [PAID]), physical activity/sedentary behaviour, alcohol consumption and diabetes self-management behaviours. Additional once-off measures at follow-up included COVID-19-specific worry, quality of life (QoL), and healthcare appointment changes (telehealth engagement and appointment cancellations/avoidance). RESULTS: Among 470 respondents (96%; aged 66 ± 9 years, 69% men), at least 'moderate' worry about COVID-19 infection was reported by 31%, and 29%-73% reported negative impacts on QoL dimensions (greatest for: leisure activities, feelings about the future, emotional well-being). Younger participants reported more negative impacts (p < 0.05). Overall, anxiety/depressive symptoms were similar at follow-up compared with pre-COVID-19, but diabetes distress reduced (p < 0.001). Worse trajectories of anxiety/depressive symptoms were observed among those who reported COVID-19-specific worry or negative QoL impacts (p < 0.05). Physical activity trended lower (~10%), but sitting time, alcohol consumption and glucose-monitoring frequency remained unchanged. 73% of participants used telehealth, but 43% cancelled a healthcare appointment and 39% avoided new appointments despite perceived need. CONCLUSIONS: COVID-19 lockdown restrictions negatively impacted QoL, some behavioural risk factors and healthcare utilisation in adults with type 2 diabetes. However, generalised anxiety and depressive symptoms remained relatively stable.

A systematic review of trends in all-cause mortality among people with diabetes.

AIMS/HYPOTHESIS: We examined all-cause mortality trends in people with diabetes and compared them with trends among people without diabetes. METHODS: MEDLINE, EMBASE and CINAHL databases were searched for observational studies published from 1980 to 2019 reporting all-cause mortality rates across ≥2 time periods in people with diabetes. Mortality trends were examined by ethnicity, age and sex within comparable calendar periods. RESULTS: Of 30,295 abstracts screened, 35 studies were included, providing data on 69 separate ethnic-specific or sex-specific populations with diabetes since 1970. Overall, 43% (3/7), 53% (10/19) and 74% (32/43) of the populations studied had decreasing trends in all-cause mortality rates in people with diabetes in 1970-1989, 1990-1999 and 2000-2016, respectively. In 1990-1999 and 2000-2016, mortality rates declined in 75% (9/12) and 78% (28/36) of predominantly Europid populations, and in 14% (1/7) and 57% (4/7) of non-Europid populations, respectively. In 2000-2016, mortality rates declined in 33% (4/12), 65% (11/17), 88% (7/8) and 76% (16/21) of populations aged <40, 40-54, 55-69 and ≥70 years, respectively. Among the 33 populations with separate mortality data for those with and without diabetes, 60% (6/10) of the populations with diabetes in 1990-1999 and 58% (11/19) in 2000-2016 had an annual reduction in mortality rates that was similar to or greater than in those without diabetes. CONCLUSIONS/INTERPRETATION: All-cause mortality has declined in the majority of predominantly Europid populations with diabetes since 2000, and the magnitude of annual mortality reduction matched or exceeded that observed in people without diabetes in nearly 60% of populations. Patterns of diabetes mortality remain uncertain in younger age groups and non-Europid populations. REGISTRATION: PROSPERO registration ID CRD42019095974. Graphical abstract.

Interrupting prolonged sitting in type 2 diabetes: nocturnal persistence of improved glycaemic control.

AIMS/HYPOTHESIS: We aimed to examine the effect of interrupting 7 h prolonged sitting with brief bouts of walking or resistance activities on 22 h glucose homeostasis (including nocturnal-to-following morning hyperglycaemia) in adults with type 2 diabetes. METHODS: This study is an extension of a previously published randomised crossover trial, which included 24 inactive overweight/obese adults with type 2 diabetes (14 men; 62 ± 6 years) who completed three 7 h laboratory conditions, separated by 6-14 day washout periods: SIT: (1) prolonged sitting (control); (2) light-intensity walking (LW): sitting plus 3 min bouts of light-intensity walking at 3.2 km/h every 30 min; (3) simple resistance activities (SRA): sitting plus 3 min bouts of simple resistance activities (alternating half-squats, calf raises, brief gluteal contractions and knee raises) every 30 min. In the present study, continuous glucose monitoring was performed for 22 h, encompassing the 7 h laboratory trial, the evening free-living period after leaving the laboratory and sleeping periods. Meals and meal times were standardised across conditions for all participants. RESULTS: Compared with SIT, both LW and SRA reduced 22 h glucose [SIT: 11.6 ± 0.3 mmol/l, LW: 8.9 ± 0.3 mmol/l, SRA: 8.7 ± 0.3 mmol/l; p < 0.001] and nocturnal mean glucose concentrations [SIT: 10.6 ± 0.4 mmol/l, LW: 8.1 ± 0.4 mmol/l, SRA: 8.3 ± 0.4 mmol/l; p < 0.001]. Furthermore, mean glucose concentrations were sustained nocturnally at a lower level until the morning following the intervention for both LW and SRA (waking glucose both -2.7 ± 0.4 mmol/l compared with SIT; p < 0.001). CONCLUSIONS/INTERPRETATION: Interrupting 7 h prolonged sitting time with either LW or SRA reduced 22 h hyperglycaemia. The glycaemic improvements persisted after these laboratory conditions and nocturnally, until waking the following morning. These findings may have implications for adults with relatively well-controlled type 2 diabetes who engage in prolonged periods of sitting, for example, highly desk-bound workers. TRIAL REGISTRATION: anzctr.org.au ACTRN12613000576729 FUNDING: : This research was supported by a National Health and Medical Research Council (NHMRC) project grant (no. 1081734) and the Victorian Government Operational Infrastructure Support scheme.

QT interval variability in type 2 diabetic patients with cardiac sympathetic dysinnervation assessed by 123I-metaiodobenzylguanidine scintigraphy.

UNLABELLED: QT Variability and Sympathetic Dysinnervation. INTRODUCTION: The mechanism of adverse prognosis attributable to proarrhythmic cardiac sympathetic dysinnervation in patients with type 2 diabetes is incompletely understood. This study sought the association of cardiac sympathetic dysinnervation with temporal instability of ventricular repolarization assessed by beat-to-beat QT interval variability. METHODS AND RESULTS: (123) I-metaiodobenzylguanidine ((123) I-MIBG) scintigraphy was analyzed in 31 type 2 diabetic patients for cardiac sympathetic dysinnervation (4-hour heart-to-mediastinum ratio <1.8) and regional sympathetic integrity and washout rate (from 15-minute (123) I-MIBG uptake). Relative QT variability was defined from a continuous 5-minute ECG in the supine position (n = 31) and standing position (subgroup; n = 15) by the log ratio of absolute QT variability (QT variance divided by the mean QT interval squared) to heart rate (HR) variability (HR variance divided by the mean HR squared). Patients with (n = 16; 52%) versus without cardiac sympathetic dysinnervation demonstrated higher relative QT variability in the supine position (P < 0.001), owing to lower HR variability. However, on standing, absolute QT variability was significantly raised in these patients (P = 0.009) despite similar HR variability in the 2 groups. Correlations of heart-to-mediastinum ratio with standing QT variability (relative [r =-0.63, P = 0.013] and absolute [r =-0.79, P = 0.001]) were superior to corresponding supine measures (relative [r =-0.47, P = 0.008] and absolute [P = NS]). No associations of QT variability with washout rate or regional (123) I-MIBG uptake were identified. CONCLUSION: Elevated QT variability is associated with cardiac sympathetic dysinnervation in type 2 diabetes and may contribute to adverse prognosis. Moreover, QT variability may be more specific for cardiac sympathetic innervation when measured in the context of sympathetic activation. (J Cardiovasc Electrophysiol, Vol. 24, pp. 305-313, March 2013).

Algorithms to define diabetes type using data from administrative databases: A systematic review of the evidence.

AIMS: To find the best-performing algorithms to distinguish type 1 and type 2 diabetes in administrative data. METHODS: Embase and MEDLINE databases were searched from January 2000 until January 2023. Papers evaluating the performance of algorithms to define type 1 and type 2 diabetes by reporting diagnostic metrics against a range of reference standards were selected. Study quality was evaluated using the Quality Assessment of Diagnostic Accuracy Studies. RESULTS: Of the 24 studies meeting the eligibility criteria, 19 demonstrated a low risk of bias and low concerns about the applicability of the study population across all domains. Algorithms considering multiple diabetes diagnostic codes alone were sensitive and specific approaches to classify diabetes type (both metrics >92.1% for type 1 diabetes; >86.9% for type 2 diabetes). Among the top 10-performing algorithms to detect type 1 and type 2 diabetes, 70% and 100% featured multiple criteria, respectively. Information on insulin use was more sensitive and specific for detecting diabetes type than were criteria based on use of oral hypoglycaemic agents. CONCLUSIONS: Algorithms based on multiple diabetes diagnostic codes and insulin use are the most accurate approaches to distinguish type 1 from type 2 diabetes using administrative data. Approaches with more than one criterion may also increase sensitivity in distinguishing diabetes type.

Clinical Utility of Cardiovascular Risk Scores for Identification of People With Type 2 Diabetes More Likely to Benefit From Either GLP-1 Receptor Agonist or SGLT2 Inhibitor Therapy.

OBJECTIVE: Differentiation of risk for major adverse cardiovascular events (MACE) from heart failure hospitalization (HHF) or kidney disease is important when selecting glucose-lowering therapy. We investigated the ability of separate MACE and HHF risk scores to 1) differentiate MACE from HHF risk; and 2) identify individuals more likely to benefit from either glucagon-like peptide-1 receptor agonists (GLP-1RAs) or sodium-glucose cotransporter-2 inhibitors (SGLT2is). RESEARCH DESIGN AND METHODS: We identified three trials in type 2 diabetes that reported cardiovascular outcomes stratified by Thrombolysis In Myocardial Infarction Risk Scores for MACE and HHF. Pooled placebo-arm rates of HHF, MACE, and their ratio and estimated GLP-1RA- and SGLT2i-mediated reductions in events (MACE and HHF combined) were compared across cardiovascular risk strata in the trial populations. RESULTS: The HHF rate was less frequent than MACE at all risk levels but increased from 18% of the MACE rate at low-intermediate HHF risk to 61% at highest HHF risk. Similarly, with increasing MACE risk, the incidence of HHF increased from 19% of the MACE incidence in those at low MACE risk to 51% in those with the highest MACE risk. Estimated GLP-1RA- and SGLT2i-mediated reductions in cardiovascular events were similar in those at low-intermediate MACE or HHF risk but tended to favor SGLT2is at higher risk levels of both scores. CONCLUSIONS: A greater increase in the rate of HHF relative to MACE was observed with progressively higher cardiovascular risk, regardless of the risk score applied. Consequently, SGLT2is may offer greater overall cardiovascular protection in those at highest MACE risk, not just those at highest HHF risk.

IDF diabetes Atlas: Global estimates of undiagnosed diabetes in adults for 2021.

AIMS: To provide up-to-date estimates of undiagnosed diabetes mellitus (UDM) prevalence - both globally, and by region/country, for the year 2021. METHODS: Data sources reporting diabetes prevalence were identified through a systematic search in the peer-reviewed and grey literature. The prevalence of undiagnosed diabetes was estimated from the data from each country where data was available. For countries without in-country data, the prevalence of undiagnosed diabetes was approximated by extrapolating the average of the estimates from countries with data sources within the same International Diabetes Federation (IDF) region and World Bank income grouping. We then applied these stratified prevalence estimates of UDM from each country to the number of adults in each strata and summed the counts to generate the number of adults with UDM (aged 20-79 years) for 215 countries and territories. RESULTS: In 2021, almost one in two adults (20-79 years old) with diabetes were unaware of their diabetes status (44.7%; 239.7 million). The highest proportions of undiagnosed diabetes (53.6%) were found in the Africa, Western Pacific (52.8%) and South-East Asia regions (51.3%), respectively. The lowest proportion of undiagnosed diabetes was observed in North America and the Caribbean (24.2%). CONCLUSIONS: Diabetes surveillance needs to be strengthened to reduce the prevalence of UDM, particularly in low- and middle-income countries.

Heart failure hospitalisation relative to major atherosclerotic events in type 2 diabetes with versus without chronic kidney disease: A meta-analysis of cardiovascular outcomes trials.

AIM: We examined whether chronic kidney disease (CKD) modifies the frequency of heart failure hospitalisation (HHF) relative to atherosclerotic major adverse cardiovascular events (MACE; composite of cardiovascular death, myocardial infarction [MI], or stroke) in people with type 2 diabetes. METHODS: Of 16 cardiovascular outcomes trials in type 2 diabetes since 2013, seven reported outcomes stratified by estimated glomerular filtration rate (eGFR) category (<60 vs. ≥60 mL/min/1.73 m2), and five by albuminuria status. Placebo-arm incidence rates of HHF, MACE, MI and stroke were extracted for each eGFR and albuminuria subgroup. RESULTS: CKD coincided with higher rates of all events, but the greatest increase was observed for HHF (2.66 times higher rate in subgroups with reduced eGFR [95% CI 2.23-3.18]; 2.69 times higher in those with albuminuria [95% CI 2.30-3.13]). By contrast, the rate of MACE was 1.78 (1.67-1.91) and 1.80 (1.57-2.07) times higher in those with reduced eGFR and albuminuria, respectively. In people with CKD, HHF occurred at a similar rate to MI (ratio of HHF:MI = 0.92 with eGFR <60, 0.94 with albuminuria), while in those without CKD, MI was significantly more common (HHF:MI = 0.58 with eGFR 60+ and 0.60 with normoalbuminuria). HHF rates exceeded stroke in people with CKD, but these events otherwise occurred at a similar rate. While reduced eGFR was associated with older age, no such differences between people with/without albuminuria explained their different event profile. CONCLUSION: CKD is associated with a shift in the profile of cardiovascular events in people with type 2 diabetes, marked by a disproportionate increase in HHF relative to MACE.

Declining mortality in older people with type 2 diabetes masks rising excess risks at younger ages: a population-based study of all-cause and cause-specific mortality over 13 years.

BACKGROUND: Excess mortality in people with vs without type 2 diabetes (T2DM) has fallen, but it is unclear whether men/women at all ages have benefited and which causes of death have driven these trends. METHODS: All-cause and cause-specific mortality rates and excess mortality [by mortality rate ratios (MRRs) relative to the non-diabetic general population] were examined in 1 268 018 Australians with T2DM registered on the National Diabetes Services Scheme (2002-2014). RESULTS: Age-standardized mortality decreased in men (-2.2%/year; Ptrend < 0.001) and women with T2DM (-1.3%/year; Ptrend < 0.001) throughout 2002-14, which translated to declines in the MRRs (from 1.51 to 1.45 in men; 1.59 to 1.46 in women; Ptrend < 0.05 for both). Declining mortality rates in T2DM were observed in men aged 40+ years and women aged 60+ years (Ptrends <0.001), but not at younger ages. However, the only age group in which excess mortality declined relative to those without diabetes was 80+ years (Ptrends < 0.05); driven by reductions in excess cancer-related deaths in men and cardiovascular disease (CVD) in women. Among age groups <80 years, CVD and cancer MRRs remained similar or increased over time, despite falls in both CVD and cancer mortality rates. MRRs for non-CVD/non-cancer-related deaths increased in 60-79 year-olds, but were otherwise unchanged. CONCLUSIONS: Declining excess mortality attributable to T2DM from 2002-14 was driven entirely by reductions in those aged 80+ years. Declines in total mortality among those with T2DM were apparent in more age groups, but often to a lesser extent than in the general population, thereby serving to increase the excess risk associated with T2DM.

Incidence of Hospitalization for Heart Failure Relative to Major Atherosclerotic Events in Type 2 Diabetes: A Meta-analysis of Cardiovascular Outcomes Trials.

BACKGROUND: Emerging evidence points to heart failure as being a common first presentation of cardiovascular (CV) disease in type 2 diabetes. PURPOSE: The purpose of this study was to determine whether hospitalization for heart failure (HHF) occurs more or less frequently than major adverse CV events (MACE) in people with type 2 diabetes. DATA SOURCES: Placebo arms of CV outcomes trials in type 2 diabetes were included. STUDY SELECTION: Sixteen CV outcomes trials were selected, including five dipeptidyl peptidase 4 inhibitor trials, seven glucagon-like peptide 1 receptor agonist trials, and four sodium-glucose cotransporter 2 inhibitor trials. DATA EXTRACTION: We extracted incidence rates of HHF, myocardial infarction (MI), stroke, and the composite outcomes of CV death or HHF and MACE (CV death, nonfatal MI, or nonfatal stroke). DATA SYNTHESIS: In two trials enriched with people with chronic kidney disease, HHF was more common than both MI and stroke. Among the remaining 14 trials, HHF was less frequent than MI in 13 (93%), with this difference being significant in 8 (57%); however, HHF surpassed stroke in all but 1 study (93%; significant in 7 studies [50%]). Heterogeneity among trials was moderate/high (I 2 >50%) and partly explained by HHF/MI correlating with age and previous MI history (P < 0.05). In seven trials that reported events stratified by presence/absence of preexisting CV disease, ratios of HHF/MI and HHF/stroke were similar between groups. LIMITATIONS: Enrichment of trial populations with those at high risk of CV events limits generalizability. CONCLUSIONS: Although less frequent than MI, HHF is a common event in type 2 diabetes, both in those with and those without prior CV disease.

Young-onset type 2 diabetes mellitus - implications for morbidity and mortality.

Accumulating data suggest that type 2 diabetes mellitus (T2DM) in younger people (aged <40 years), referred to as young-onset T2DM, has a more rapid deterioration of ß-cell function than is seen in later-onset T2DM. Furthermore, individuals with young-onset T2DM seem to have a higher risk of complications than those with type 1 diabetes mellitus. As the number of younger adults with T2DM increases, young-onset T2DM is predicted to become a more frequent feature of the broader diabetes mellitus population in both developing and developed nations, particularly in certain ethnicities. However, the magnitude of excess risk of premature death and incident complications remains incompletely understood; likewise, the potential reasons for this excess risk are unclear. Here, we review the evidence pertaining to young-onset T2DM and its current and future burden of disease in terms of incidence and prevalence in both developed and developing nations. In addition, we highlight the associations of young-onset T2DM with premature mortality and morbidity.

Left Ventricular Dysfunction and Exercise Capacity Trajectory: Implications for Subclinical Heart Failure Staging Criteria.

OBJECTIVES: This study aimed to determine the association of stage B heart failure (SBHF) and its constituent left ventricular (LV) abnormalities with trajectory of exercise capacity over time, and assess whether this association is modified by reversion of these LV abnormalities to normal. BACKGROUND: The LV abnormalities of SBHF may coincide with a reduction in exercise capacity that precedes the overt exercise intolerance of clinical heart failure (HF). Determining the predictive capacity of established and novel SBHF criteria for exercise capacity decline may improve HF risk stratification. METHODS: LV structure/function (echocardiography) and exercise capacity (6-min walk distance [6MWD]) were assessed at baseline and 3-year follow-up in 268 patients from the NIL-CHF (Nurse-led Intervention for Less Chronic Heart Failure) study (all stage A [SAHF] or SBHF). Changes (Δ) in 6MWD were compared between SAHF and SBHF and across each of 4 constituent components of SBHF: LV hypertrophy, regional wall motion abnormality(ies) (RWMA), left ventricular systolic dysfunction (LVSD) (ejection fraction <45%) and elevated early diastolic filling/annular velocity ratio (E/e' ≥15). RESULTS: Δ6MWD was similar in those with SAHF (n = 141) and SBHF (n = 127; -5 m [95% confidence interval (CI): -21 to +11 m]; covariate-adjusted). However, within the setting of SBHF there was substantive heterogeneity; that is, reductions in 6MWD were observed with persistent elevated E/e' (-34 m [95% CI: -62 to -6 m]) and persistent LVSD (-41 m [95% CI: -74 to -8 m]), but not with LV hypertrophy (+17 m [95% CI: -15 to +49 m) or RWMA (+5 m [-27 to +36 m]), nor in patients whose elevated E/e' or LVSD reverted to normal by 3 years (p > 0.10). CONCLUSIONS: Elevated E/e' is associated with a similar degree of exercise capacity decline to LVSD, supporting that both LV functional criteria be considered in distinguishing SBHF from SAHF. That reversion of either manifestation of LV dysfunction was associated with preserved exercise capacity advocates targeting of these factors by HF preventive interventions.

Associations of Chronic Kidney Disease Markers with Cognitive Function: A 12-Year Follow-Up Study.

BACKGROUND: The role of chronic kidney disease (CKD) as a risk factor for cognitive impairment independent of their shared antecedents remains controversial. OBJECTIVE: To determine whether kidney damage (indicated by albuminuria) or kidney dysfunction (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2) predict future (12-year) cognitive function independently of their shared risk factors. METHODS: We studied 4,128 individuals from the 1999/00 population-based Australian Diabetes, Obesity, and Lifestyle (AusDiab) Study who returned in 2011/12 for follow-up cognitive function testing. Albuminuria was defined by urinary albumin:creatinine≥3.5 (women) or≥2.5 mg/mmol (men). Kidney dysfunction was indicated by eGFR <60 ml/min/1.73 m2. Cognitive function domains assessed included memory (California Verbal Learning Test [CVLT]) and processing speed (Symbol Digit Modalities Test [SDMT]). RESULTS: Baseline albuminuria and kidney dysfunction were identified in 142 (3.4%) and 39 (0.9%) individuals, respectively, with minimal overlap (n = 7). Those with albuminuria demonstrated concurrently reduced 12-year SDMT (p = 0.084) and CVLT scores (p = 0.005) following adjustment for age, sex, and education. However, only CVLT performance remained worse (p = 0.027) following additional adjustment for myocardial infarction, stroke, and related risk factors (hypertension, diabetes, dyslipidemia, smoking, BMI, physical activity, and alcohol intake). Indeed, these collective covariates were responsible for 47% of the effect of albuminuria on SDMT, but only 21% of its effect on CVLT. Kidney dysfunction was not associated with either SDMT or CVLT performance (p > 0.10). CONCLUSIONS: Albuminuria predicted worse memory function at 12 years follow-up, whereas its effect on processing speed was driven largely by differences in cardiovascular risk. Kidney dysfunction based on eGFR predicted neither cognitive domain.

Pulse wave analysis is a reproducible technique for measuring central blood pressure during hemodynamic perturbations induced by exercise.

BACKGROUND: Central blood pressure (BP) and markers of wave reflection (augmentation index; AIx) measured by radial tonometry have prognostic value independent from brachial BP. The measurement of the central waveform is increasingly used during altered hemodynamics, including exercise, but reliability of the test has not been reported under changed loading conditions. This study aimed to test the technique's reproducibility during major hemodynamic perturbations induced by exercise. METHODS: Radial waveforms were recorded (SphygmoCor) in 28 healthy subjects (aged 53 +/- 11 years) at rest, during submaximal exercise (cycling at 50, 60, and 70% of maximal age-predicted heart rate (HR)) and immediately after maximal treadmill exercise on two occasions separated by 9 +/- 5 days. Data were compared between testing days. Waveforms were calibrated with brachial BP measured using a mercury sphygmomanometer. Pulse pressure amplification (PPAmp) was defined as the ratio of brachial to central pulse pressure. RESULTS: There was very good reproducibility between visits at all exercise intensities for all waveform measures, including AIx, central pulse pressure, and PPAmp (intraclass correlations at 50% exercise were 0.93, 0.89, and 0.89, respectively; P < 0.001). The mean difference between tests at this intensity was 0 +/- 4% for AIx, 4 +/- 6 mm Hg for central pulse pressure, and -0.02 +/- 0.09 for PPAmp. There were no significant differences between visits for HR, PPAmp, or AIx at rest or with exercise (P > 0.05 for all). CONCLUSIONS: Radial tonometry is a reproducible technique for measurement of central waveform indices during perturbations induced by exercise. It should, therefore, be suitable for use in intervention studies in which hemodynamics are altered.

Mild cognitive impairment is associated with subclinical diastolic dysfunction in patients with chronic heart disease.

Background: To examine mild cognitive impairment and its associations with subclinical cardiac dysfunction in patients with chronic heart disease yet to develop the clinical syndrome of chronic heart failure (CHF). Methods and results: Patients from the Nurse-led Intervention for Less Chronic Heart Failure Study (n = 373 with chronic heart disease other than CHF; 64 ± 11 years, 69% men) were screened for mild cognitive impairment [Montreal cognitive assessment (MoCA) score <26] and underwent echocardiographic/clinical profiling. We investigated associations of mild cognitive impairment and MoCA cognitive domain subscores with global cardiac status ('normal' vs. 'diastolic dysfunction' vs. 'other cardiac abnormality') and individual echocardiographic parameters. Patients with mild cognitive impairment (n = 161; 43%) demonstrated a higher age-adjusted prevalence of diastolic dysfunction (37% vs. 24%; P < 0.05). Multivariate logistic regression (adjusted for age, sex, and other relevant clinical factors) indicated that the odds of mild cognitive impairment were two-times higher with diastolic dysfunction (P = 0.030) and 1.7-times higher with 'other cardiac abnormalities' (P = 0.082) vs. normal cardiac status. In turn, mild cognitive impairment was predicted by left-ventricular (LV) filling pressure (based on the ratio of early diastolic filling and annular velocities; adjusted odds ratio 1.07 per unit increase, P = 0.022), but not LV structural parameters. Specific deficits in the cognitive domains of executive functioning and visuo-constructional abilities were also independently predicted by diastolic dysfunction (P < 0.05). Conclusion: Mild cognitive impairment is prevalent in patients with subclinical chronic heart disease at high-risk of CHF. Independent associations with LV diastolic dysfunction suggest a link between cardiac and cognitive functioning beyond shared risk factors.