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OBJECTIVE Cardiovascular risk reduction is an important focus in the management of people with diabetes. Although event rates have been declining over the long term, they have been observed to plateau or reverse in recent years. Furthermore, the impact of income-related disparities in cardiovascular events is unknown. The objective of this study is to evaluate age-, sex-, and income-related trends in cardiovascular hospitalization rates among people with diagnosed diabetes. RESEARCH DESIGN AND METHODS We calculated rates of hospitalization for acute myocardial infarction, stroke, heart failure, and lower-extremity amputation in annual cohorts of the entire population of Ontario, Canada, with diagnosed diabetes, from 1995 to 2019. Event rates were stratified by age, sex, and income level. RESULTS We studied nearly 1.7 million people with diabetes. The rate of acute myocardial infarction declined throughout the 25-year study period (P < 0.0001), such that the rate in 2019 was less than half the rate in 1995. Rates of stroke (P < 0.0001), heart failure (P < 0.0001), and amputation (P < 0.0001) also changed over time, but hospitalization rates stabilized through the 2010s. This apparent stabilization concealed a growing income-related disparity: wealthier patients showed continued declines in rates of these outcomes during the decade, whereas rates for lower-income patients increased (P for interaction < 0.0001 for all four outcomes). CONCLUSIONS During a quarter-century of follow-up, cardiovascular hospitalization rates among people with diabetes fell. However, the apparent stabilization in rates of stroke, heart failure, and amputation in recent years masks the fact that rates have risen for lower-income individuals.

Objective: Cardiovascular risk reduction is an important focus in the management of people with diabetes. Although event rates have been declining over the long-term, they have been observed to plateau or reverse in recent years. Furthermore, the impact of income-related disparities in cardiovascular events is unknown. The objective of this study was to evaluate age-, sex- and income-related trends in cardiovascular hospitalization rates among people with diagnosed diabetes. Research Design and Methods: We calculated rates of hospitalization for acute myocardial infarction, stroke, heart failure and lower extremity amputation in annual cohorts of the entire population of Ontario, Canada with diagnosed diabetes, from 1995 to 2019. Event rates were stratified by age, sex and income level. Results: We studied nearly 1.7 million people with diabetes. The rate of acute myocardial infarction declined throughout the 25-year study period (p Conclusions: During a quarter-century of follow-up, cardiovascular hospitalization rates among people with diabetes fell. However, the apparent stabilization in rates of stroke, heart failure and amputation in recent years masks the fact that rates have risen for lower-income individuals.

Objective There has been growing interest in the potential role for allopurinol to reduce cardiovascular events in people with diabetes. While adherence to allopurinol is poor in those with gout, our aim was to characterize persistence, patterns of use, and predictors of allopurinol use in a population-based cohort of individuals with diabetes and gout. Methods Individuals with diabetes older than 66 (thus eligible for prescription medication coverage) and newly prescribed allopurinol were followed for up to three years in a retrospective cohort study. Allopurinol use patterns were categorized as adherer (used continuously throughout follow-up), interrupter (non-persistent but subsequently resumed), or discontinuer (non-persistent with no subsequent resumption). Main outcomes were allopurinol non-persistence (no subsequent prescription accounting for a grace period), and indicators of gout severity throughout follow-up (prescriptions for prednisone or colchicine, outpatient gout visits, hospitalization/emergency department visits for gout). Outcome frequencies were determined, a multivariable Cox proportional hazards model evaluated associations between predictors and non-persistence, and zero-inflated negative binomial (ZINB) models evaluated associations between allopurinol use pattern and indicators of gout severity. Results 22,056 individuals were followed for a maximum of 3.0 years (17,410 with 3 years of follow-up). 9092 (41.2%) were non-persistent with allopurinol. Higher risks of non-persistence were associated with female sex (HR, 95% CI: 1.28, 1.23–1.33), dementia (1.23, 1.11–1.35), and an outpatient visit for gout in the prior year (1.19, 1.09–1.29). There were 12,964 (58.8%) allopurinol adherers, 4618 interrupters (20.9%), and 4474 (20.3%) discontinuers. Allopurinol interrupters and discontinuers had indicators of more severe gout over time compared to adherers, including greater odds of being prescribed prednisone. Conclusion Allopurinol non-persistence and interruptions were frequent in individuals with diabetes and gout and were associated with prescriptions for prednisone. Suboptimal allopurinol adherence may not only increase the risk of gout complications in this population but also potentially diabetes complications through greater prednisone use and its negative effects on glycemic control.

ObjectivesType 2 diabetes (T2DM) and knee osteoarthritis (OA) commonly co-occur and epidemiologic studies suggest concomitant symptomatic knee OA increases the risk of T2DM complications. We sought to explore the experiences and perspectives of individuals’ living with both symptomatic knee OA and T2DM, with a focus on the impact of OA on T2DM management and daily life.DesignWe conducted qualitative semistructured telephone interviews with persons living with T2DM and knee OA. We inductively coded and analysed interview transcripts, informed by interpretative description.SettingWe recruited participants from a community arthritis self-management programme and an academic hospital’s family medicine clinic in Ontario, Canada.ParticipantsWe included 18 participants who had a physician diagnosis of both T2DM and knee OA, with variation age, gender, and duration of T2DM and knee OA.ResultsParticipants with T2DM described how concomitant painful and disabling knee OA made it difficult to engage in physical activity, negatively impacting blood glucose control. Joint pain itself, associated sleep disturbance and emotional distress were also seen to affect blood glucose control. Beyond diabetes management, the impact of OA-related pain and functional limitations on nearly all aspects of daily life led participants to view their OA as important. Despite this, many participants described that their health professionals paid little attention to their OA, which left them to self-manage. Balancing both conditions also required navigating a medical system that provided piecemeal care.ConclusionsIndividuals with T2DM view symptomatic knee OA as an important barrier to both T2DM management and overall well-being, yet are frequently met with insufficient support from health professionals. Greater recognition and management of knee OA in persons with T2DM could help improve patient-centred care and potentially disease outcomes.

ObjectiveDelivering person-centered care in individuals with knee osteoarthritis (OA) necessitates consideration of other chronic conditions that frequently co-occur. We sought to understand the extent to which arthritis therapists consider type 2 diabetes mellitus (T2DM) when treating persons with knee OA and concomitant T2DM, and barriers to doing so.MethodsWe conducted 18 semistructured telephone interviews with arthritis therapists working within a provincially funded arthritis care program (Arthritis Society Canada) in Ontario, Canada. We first analyzed interviews deductively using the Theoretical Domains Framework (TDF) to comprehensively identify barriers and enablers to health behaviors. Then, within TDF domains, we inductively developed themes.ResultsWe identified 5 TDF domains as prominently influencing the behavior of arthritis therapists considering concomitant T2DM when developing a knee OA management plan. These were as follows: therapists’ perceived lack of specific knowledge around comorbidities including diabetes; the lack of breadth in skills in behavioral change techniques to help patients set and reach their goals, particularly when it came to physical activity; variable intention to factor a patient’s comorbidity profile to influence their treatment recommendations; the perception of their professional role and identity as joint focused; and the environmental context with lack of formalized follow-up structure of the current Arthritis Society Canada program that limited sufficient patient monitoring and follow-up.ConclusionWithin the context of a Canadian arthritis program, we identified several barriers to arthritis therapists considering T2DM in their management plan for persons with knee OA and T2DM. These results can help inform strategies to improve person-centered OA care and overall health outcomes.

To determine the relationship between renal hemodynamic function and neuropathy in adults with ≥50-years of type 1 diabetes (T1D) compared to nondiabetic controls.Glomerular filtration rate (GFR, inulin), effective renal plasma flow (ERPF, p-aminohippurate), modified Toronto Clinical Neuropathy Score (mTCNS), corneal confocal microscopy, nerve conduction, and heart rate variability (autonomic function) were measured; afferent (RHigher mTCNS associated with lower renal blood flow (β ± SE:-9.29 ± 4.20, p = 0.03) and greater RAlthough neurological dysfunction in the presence of diabetes may contribute to impaired renal blood flow resulting in ischemic injury in patients with T1D, early autonomic dysfunction does not appear to be associated with kidney function changes.

Patients with diabetes and co-existing chronic kidney disease and/or cardiovascular disease have complex medical needs with multiple indications for different guideline-directed medical therapies and require high health care resource utilization. The Cardiac and Renal Endocrine Clinic (C.a.R.E. Clinic) is a multi- and interdisciplinary clinic offering a unique care model to this population to overcome barriers to optimal care.To describe the patient characteristics and clinical data of consecutive patients seen in the C.a.R.E. Clinic between 2014 and 2020, with a focus on the feasibility, strengths, and challenges of this outpatient care model.Single-center retrospective cohort study.The C.a.R.E. Clinic is a multi- and interdisciplinary clinic at Toronto General Hospital in Toronto, Canada.We reviewed the charts of all 118 patients who had been referred to the C.a.R.E. Clinic with type 2 diabetes mellitus, co-existing renal disease, and/or cardiovascular disease.Demographic data, medication data, clinic blood pressure measurements, and laboratory data were assessed at the first and last available clinic visit.Data were extracted via manual chart review of paper and electronic medical records.First and last attended clinic visit data were available for descriptive analysis in 74 patients. There was a significant improvement in low-density lipoprotein (LDL) cholesterol (1.9 mmol/L vs 1.5 mmol/L,This is a retrospective chart review lacking a control group, therefore clinical improvements cannot be causally attributed to the clinic alone. New evidence and changes to guideline-recommended therapies also contributed to practice changes during this time period.A multi- and interdisciplinary clinic is a feasible and potentially effective way to improve evidence-based and patient-centered care for patients with diabetes, kidney, and cardiovascular disease.Les patients diabétiques présentant une néphropathie chronique et/ou maladie cardiovasculaire co-existante ont des besoins complexes avec de multiples indications concernant différents traitements médicaux recommandés par les lignes directrices. En outre, ces patients nécessitent une utilisation élevée des ressources de santé. La clinique C.a.R.E. (Décrire les caractéristiques et les données cliniques des patients consécutifs suivis à la clinique C.a.R.E. entre 2014 et 2020, en se concentrant sur la faisabilité et sur les avantages et les défis de ce modèle de soins ambulatoires.Étude de cohorte rétrospective menée dans un seul centre.La clinique C.a.R.E. est une clinique multidisciplinaire et interdisciplinaire de l’Hôpital général de Toronto (Canada).Nous avons examiné les dossiers des 118 patients diabétiques de type 2 atteints d’une néphropathie et/ou maladie cardiovasculaire qui ont été dirigés vers la clinique C.a.R.E. au cours de la période étudiée.Les données démographiques, les données sur les ordonnances, les mesures cliniques de la pression artérielle et les données de laboratoire ont été évaluées pour la première et la dernière visite à la clinique disponibles.Les données ont été extraites par un examen manuel des dossiers médicaux papier et électronique.Les données d’intérêt pour la première et la dernière visite à la clinique étaient disponibles pour l’analyse descriptive chez 74 patients. Entre la première et la dernière visite disponible, on a observé une amélioration significative du taux de cholestérol LDL (1,9 mmol/L vs 1,5 mmol/L; p0,01), de l’hémoglobine A1c (7,5 % vs 7,1 %; p = 0,02) et de la proportion de patients avec une mesure de pression artérielle dans les valeurs cibles (52,7 % vs 36,5 %; p = 0,04) alors que l’indice de masse corporelle est demeuré inchangé (29,7 kg/m² vs 29,6 kg/m²; p = 0,15). Les ordonnances de thérapies fondées sur les données probantes ont été plus fréquentes, notamment pour les statines (93,2 % vs 81,1 %; p = 0,01), le SGLT-2i (35,1 % vs 4,1 %; p0,01) et les agonistes des récepteurs GLP-1 (13,5 % vs 4,1 %; p = 0,02); l’utilisation d’inhibiteurs du SRAA était déjà élevée au départ (81,8 % vs 78,4 %; p = 0,56). De grandes possibilités de traitement demeurent pour les inhibiteurs du cotransporteur-2 de sodium-glucose et les agonistes des récepteurs du peptide-1 de type glucagon.Il s’agit d’un examen rétrospectif des dossiers sans groupe témoin; les améliorations cliniques ne peuvent être attribuées de façon causale à la clinique seule. Pendant la période étudiée, de nouvelles données probantes et des changements aux traitements recommandés par les lignes directrices ont également entraîné des changements dans la pratique.Une clinique multidisciplinaire et interdisciplinaire est une solution viable et potentiellement efficace pour améliorer les soins axés sur les patients et les traitements fondés sur les données probantes pour les patients diabétiques atteints de néphropathie et/ou de maladies cardiovasculaires.

This study uses administrative health care data from Ontario, Canada, to assess whether changes in diabetes management practices have affected trends in the association between diabetes vs prior cardiovascular disease and risk of cardiovascular events from 1994 to 2019 among adults aged 20 to 84 years.

Introduction: Glomerular filtration rate (GFR) is routinely used for clinical assessment of kidney function. However, the accuracy of estimating equations in older adults is uncertain. Methods: In 66 adults with ≥50 years type 1 diabetes (T1D) duration and 73 nondiabetic controls from age/sex-matched subgroups (65 ± 8 years old and 77[55%] were women) we evaluated the performance of estimated GFR (eGFR) by creatinine (Modification of Diet and Renal Disease [MDRD], Chronic Kidney Disease–Epidemiology [CKD-EPI]cr), cystatin C (CKD-EPIcys, CKD-EPIcr-cys), and β2-microglobulin (β2M) compared with measured GFR by inulin clearance (mGFR). Performance was evaluated using metrics of bias (mean difference), precision (SD), and accuracy (proportion of eGFR that differed by >20% of mGFR). Results: Mean mGFR was 104 ± 18 ml/min per 1.73 m2 (range: 70–154 ml/min per 1.73 m2) and was not different between T1D and controls (103 ± 17 vs. 105 ± 19 ml/min per 1.73 m2, P = 0.39). All equations significantly underestimated mGFR (bias: −15 to −30 ml/min per 1.73 m2, P < 0.001 for all comparisons) except for β2M, which had bias of 1.9 ml/min per 1.73 m2 (P = 0.61). Bias was greatest in cystatin C–based equations. Precision was lowest for β2M (SD: 43.5 ml/min per 1.73 m2, P < 0.001 for each comparison). Accuracy was lowest for CKD-EPIcysC (69.1%, P < 0.001 for each comparison). Cystatin C–based equations demonstrated greater bias and lower accuracy in older age subgroups (

AIMS To examine the relationship between normal plasma uric acid (PUA) levels, renal haemodynamic function, arterial stiffness and plasma renin and aldosterone over a wide range of type 1 diabetes (T1D) durations in adolescents, young adults and older adults. MATERIALS AND METHODS PUA, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), vascular stiffness parameters (aortic augmentation index [AIx], carotid AIx, carotid femoral pulse wave velocity [cfPWV]), and plasma renin and aldosterone were measured during a euglycaemic clamp in people with T1D: 27 adolescents (mean ± SD age 16.8 ± 1.9 years), 52 young adults (mean ± SD age 25.6 ± 5.5 years) and 66 older adults (mean ± SD age 65.7 ± 7.5 years). RESULTS PUA was highest in patients with the longest T1D duration: 197 ± 44 μmol/L in adolescents versus 264 ± 82 μmol/L in older adults (P

AIM To compare glycaemic control and adverse outcomes between transition-aged and early adults with type 1 diabetes, and the impact of continuous subcutaneous insulin infusion (CSII) therapy funded through a government Assisted Devices Program. METHODS This retrospective cohort study using healthcare administrative databases from Ontario, Canada included adults aged 18-35 with type 1 diabetes between 1 April 2011 and 31 March 2014. Mean HbA1c was compared between transition-aged (18-24 years) and early adults (25-35 years), overall and stratified by whether or not they received government-funded CSII therapy (CSII vs. non-CSII). Secondary outcomes included rates of hospitalizations/emergency department visits for hyperglycaemia and hypoglycaemia over a 3-year follow-up. Comparisons were adjusted for relevant covariates. RESULTS Among 7157 participants with type 1 diabetes, mean HbA1c was significantly higher for transition-aged compared to early adults (71 mmol/mol [8.68%] vs. 64 mmol/mol [8.04%], p

Objective: International societies and clinical practice guidelines recommend a Hemoglobin A1c target of ≤7.0% for the majority of adults with type 1 (T1D) and type 2 diabetes (T2D). However, the proportion meeting this target and its predictors have not been comprehensively described outside of the USA or in population-based data sources. Methods: Adults with diabetes were identified in the National Diabetes Repository, a primary care electronic medical record (EMR) database from 5 Canadian provinces, from January 2015 to June 2019. Individuals were categorized as T1D (using a previously validated algorithm), T2D not prescribed insulin, or T2D prescribed insulin. Using the most recent HbA1c, proportions of individuals with HbA1c ≤7.0% were determined and compared using Chi-square tests. Multivariable logistic regression models were used to assess the association between predictors and meeting the HbA1c target. Results: Of 83,273 eligible adults in the National Diabetes Repository, 1484 had T1D, 10,473 had T2D prescribed insulin and 71,316 had T2D not prescribed insulin. Proportions meeting the HbA1c target of ≤7.0% were 23.9%, 24.9%, and 62.4%, respectively (p=0.4 for T1D vs. T2D prescribed insulin, p Conclusions: In a Canadian population-based primary-care EMR database, less than one-fourth of adults with T1D and T2D prescribed insulin, whereas two-thirds of adults with T2D not prescribed insulin, attain the recommended HbA1c target of ≤7.0%. Further research and implementation approaches are required to optimize outcomes in diabetes, particularly for those requiring insulin. Disclosure A. Weisman: None. B. A. Perkins: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim International GmbH, Insulet Corporation, Novo Nordisk Canada Inc., Other Relationship; Self; Abbott Diabetes, Medtronic, Novo Nordisk Canada Inc. Funding Diabetes Action Canada

Physical activity (PA) is recommended for patients with diabetes to improve glycemic control. In prediabetes and T2D there is a causal relationship between PA and peripheral nerve health; however, the effect of PA on nerve structure and function in longstanding T1D is unclear. We aimed to determine the relationship between PA and small nerve fiber morphology, large nerve fiber function and cardiac autonomic function in this population. Data from 75 participants was collected as part of the Canadian Study of Longevity in T1D. Participants completed a physical exam, medical history and neuropathy assessment including nerve conduction studies (NCS), corneal confocal microscopy measurement of corneal nerve fiber length (CNFL) and assessment of heart rate variability. Participants also reported their daily PA from the preceding 12-months. There were 41(55%) female participants, mean ± SD age was 66 ± 8 years, median duration of diabetes was 54 [52,58] years, BMI was 26.6 ± 3.8, HbA1c of 7.3 ± 0.8. 65(89%) participants met the criteria for diagnosis of diabetic neuropathy. The weekly mean PA time was 156 ± 132 min and 35(47%) reported ≧150 minutes/week. PA time was associated with a greater cooling detection threshold (r=0.24; p=0.043), higher peroneal and sural amplitude (r=0.36; p=0.0017, rs=0.26; p=0.024) and conduction velocity (rs=0.28; p=0.015, r=0.23; p=0.050). Vibration perception threshold at the toe was inversely associated with PA (r=-0.31; p=0.025), whereas there was no association at the finger. There was no association between PA time and heart rate variability (r=-0.040; p=0.74) or CNFL (r=0.23; p=0.055). Linear regression for NCS, adjusting for age and A1c, showed that for each 30 min of PA there was an 0.09 mv higher peroneal amplitude (p=0.032) and 0.048 ms lower peroneal F-wave latency (p=0.022). In individuals with longstanding T1D, PA is associated with substantially better large nerve fiber function in the lower limbs and some better measures of small nerve fiber function. Disclosure E. J. H. Lewis: Board Member; Self; Nutarniq Corp, Board Member; Spouse/Partner; Nutarniq Corp, Research Support; Self; Canadian Institutes of Health Research. B. A. Perkins: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim International GmbH, Insulet Corporation, Novo Nordisk Canada Inc., Other Relationship; Self; Abbott Diabetes, Medtronic, Novo Nordisk Canada Inc. L. Lovblom: None. S. O. Lanctot: None. D. Scarr: None. N. Cardinez: None. A. Weisman: None. M. H. Brent: Advisory Panel; Self; Novartis Pharmaceuticals Canada Inc., Roche Canada, Research Support; Self; Bayer AG, Novartis Pharmaceuticals Canada Inc. V. Bril: Advisory Panel; Self; Akcea Therapeutics, Alnylam Pharmaceuticals, Inc., CSL Behring, Sanofi Genzyme, Consultant; Self; Janssen Research & Development, LLC, Research Support; Self; Takeda Canada. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. Funding JDRF (17-2013-312)

We read with great interest the manuscript by Suissa et al that reviewed observational studies of the association between allopurinol and mortality in individuals with gout (1). Suissa describes immeasurable time bias as time periods during which prescription medication records are not available (e.g. hospitalizations), leading to at-risk time being potentially misclassified as unexposed-time. Suissa recommends accounting for the possibility of immeasurable time bias by evaluating hospitalizations during follow-up or using an analytic approach that is weighted by measurable time (2).

Objectives Elevated uric acid (UA) is common in diabetes and is implicated in the pathogenesis of chronic kidney disease (CKD). Lowering UA with allopurinol may delay CKD progression. We assessed the association between allopurinol and renal outcomes in older adults both with and without diabetes, and whether this differed by diabetes status. Methods We conducted a population-based, retrospective cohort study of older adults ≥66 years of age with a gout flare using administrative data from Ontario, Canada. The primary outcome was doubling of creatinine or kidney failure. Secondary outcomes were a composite of death or kidney failure, decline in estimated glomerular filtration rate by >30%, death and kidney failure. New allopurinol users were compared with nonusers using Cox proportional hazards models and inverse probability of treatment weighting (IPTW). An interaction between allopurinol use and presence or absence of diabetes was assessed. Results Among 5,937 older adults with a gout flare (1,911 with diabetes), 1,304 (22%) were newly treated with allopurinol. Median follow-up time was 1.11 (interquartile range, 0.33 to 3.21) years for allopurinol users and 3.38 (interquartile range, 1.42 to 4.43) years for nonusers. There was no association between allopurinol use and the primary outcome (IPTW-adjusted hazard ratio, 0.97; 95% confidence interval, 0.72 to 1.31), and this did not differ by diabetes status. Allopurinol use was not associated with any of the secondary outcomes. Conclusions Allopurinol use was not associated with renal outcomes in older adults with or without diabetes. This supports the interpretation of UA as a biomarker of CKD risk rather than a modifiable target for prevention or treatment of CKD.

Across jurisdictions, government and health insurance providers hold a large amount of data from patient interactions with the healthcare system. We aimed to develop a machine learning-based model for predicting adverse outcomes due to diabetes complications using administrative health data from the single-payer health system in Ontario, Canada. A Gradient Boosting Decision Tree model was trained on data from 1,029,366 patients, validated on 272,864 patients, and tested on 265,406 patients. Discrimination was assessed using the AUC statistic and calibration was assessed visually using calibration plots overall and across population subgroups. Our model predicting three-year risk of adverse outcomes due to diabetes complications (hyper/hypoglycemia, tissue infection, retinopathy, cardiovascular events, amputation) included 700 features from multiple diverse data sources and had strong discrimination (average test AUC = 77.7, range 77.7–77.9). Through the design and validation of a high-performance model to predict diabetes complications adverse outcomes at the population level, we demonstrate the potential of machine learning and administrative health data to inform health planning and healthcare resource allocation for diabetes management.

The relationship between renal function and neuropathy is not well established in T1D. Our objective was to determine the relationship between renal hemodynamic function and neuropathy in adults with a ≥50-year history of T1D compared to nondiabetic controls. GFR (inulin), effective renal plasma flow (ERPF, p-aminohippurate) and modified Toronto Clinical Neuropathy Score (mTCNS) were measured in 66 patients with T1D for ≥50-years and in 73 patients without diabetes matched for age and sex. Afferent (RA), efferent (RE) arteriolar resistances and glomerular hydrostatic pressure (PGLO) were estimated using Gomez’s equations. Presence of DKD was defined as eGFRMDRD30mg/day at the screening visit. Linear regressions were applied to examine the relationships between renal function (dependent variable) and measures of neuropathy (independent variable), adjusted for age, sex and HbA1c in participants with T1D and for age and sex in nondiabetic controls. Greater mTCNS, a measure of neuropathy signs and symptoms, was associated with lower renal blood flow (β=-9.57±4.15, p=0.024) and greater RE (β=32.79±15.13, p=0.034) in adults with T1D after adjusting for age, sex and HbA1c. Participants with T1D and DKD had a greater mTCNS compared to those without DKD (6.3±5.2 vs. 3.8±3.6, p=0.016). In contrast, renal hemodynamic parameters did not associate with measures of neuropathy in nondiabetic controls in multivariable models. Neuropathy score was associated with lower renal perfusion in adults with longstanding T1D. Neurological dysfunction in the presence of diabetes may contribute to impaired renal perfusion resulting in ischemic injury in patients with T1D. Further work is required to understand factors - including the autonomic nervous system - that contribute to maintaining normal renal perfusion in longstanding T1D. Disclosure Y. Lytvyn: None. P. Bjornstad: Advisory Panel; Self; XORTX Therapeutics Inc. Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Novo Nordisk Foundation. Research Support; Self; Horizon Pharma. L. Lovblom: None. H. Liu: None. J.A. Lovshin: Consultant; Self; AstraZeneca. Consultant; Spouse/Partner; Bayer Inc. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk Inc. Research Support; Self; Novo Nordisk Inc. G. Boulet: Advisory Panel; Self; Medtronic. M. Farooqi: None. A. Weisman: None. H.A. Keenan: None. M.H. Brent: Advisory Panel; Self; Bayer AG, Novartis Pharmaceuticals Canada Inc., Roche Canada. N. Paul: None. V. Bril: Advisory Panel; Self; Alexion Pharmaceuticals, Inc., Alnylam Pharmaceuticals, Takeda Canada. Consultant; Self; Akcea Therapeutics, CSL Behring, Sanofi. Research Support; Self; Biogen, Grifols, Momenta Pharmaceuticals. B.A. Perkins: Consultant; Self; Abbott, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Other Relationship; Self; Medtronic. D. Cherney: Research Support; Self; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. Other Relationship; Self; from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS and Novo-Nordisk.

IntroductionWe aimed to develop algorithms distinguishing type 1 diabetes (T1D) from type 2 diabetes in adults ≥18 years old using primary care electronic medical record (EMRPC) and administrative healthcare data from Ontario, Canada, and to estimate T1D prevalence and incidence.Research design and methodsThe reference population was a random sample of patients with diabetes in EMRPC whose charts were manually abstracted (n=5402). Algorithms were developed using classification trees, random forests, and rule-based methods, using electronic medical record (EMR) data, administrative data, or both. Algorithm performance was assessed in EMRPC. Administrative data algorithms were additionally evaluated using a diabetes clinic registry with endocrinologist-assigned diabetes type (n=29 371). Three algorithms were applied to the Ontario population to evaluate the minimum, moderate and maximum estimates of T1D prevalence and incidence rates between 2010 and 2017, and trends were analyzed using negative binomial regressions.ResultsOf 5402 individuals with diabetes in EMRPC, 195 had T1D. Sensitivity, specificity, positive predictive value and negative predictive value for the best performing algorithms were 80.6% (75.9–87.2), 99.8% (99.7–100), 94.9% (92.3–98.7), and 99.3% (99.1–99.5) for EMR, 51.3% (44.0–58.5), 99.5% (99.3–99.7), 79.4% (71.2–86.1), and 98.2% (97.8–98.5) for administrative data, and 87.2% (81.7–91.5), 99.9% (99.7–100), 96.6% (92.7–98.7) and 99.5% (99.3–99.7) for combined EMR and administrative data. Administrative data algorithms had similar sensitivity and specificity in the diabetes clinic registry. Of 11 499 711 adults in Ontario in 2017, there were 24 789 (0.22%, minimum estimate) to 102 140 (0.89%, maximum estimate) with T1D. Between 2010 and 2017, the age-standardized and sex-standardized prevalence rates per 1000 person-years increased (minimum estimate 1.7 to 2.56, maximum estimate 7.48 to 9.86, pConclusionsPrimary care EMR and administrative data algorithms performed well in identifying T1D and demonstrated increasing T1D prevalence in Ontario. These algorithms may permit the development of large, population-based cohort studies of T1D.

Physical activity (PA) is recommended to improve glycemic control in T1D; however, the effect of PA on distal symmetric polyneuropathy (DSPN) and cardiac autonomic function in longstanding T1D is unknown.Data from 75 participants were collected as part of the Canadian Study of Longevity in T1D. Participants completed a physical exam, medical history, extensive complications phenotyping and reported their daily PA from the preceding 12-months. Pearson and Spearman correlations were used to assess PA time and complications variables. Linear regression was used to test associations between PA time, neurological and electrophysiological measures. Univariable regression was used to indicate the change in the given independent variables associated with a 30-min increase in PA per week.Participants were 66 ± 8 years old with diabetes duration of 54 [52,58] years, HbAIn longstanding T1D, PA time is associated with superior large nerve fibre function in the lower limbs and some better measures of small nerve fibre function.

OBJECTIVE Our aim was to define the relationships between plasma biomarkers of kidney injury and intrarenal haemodynamic function (glomerular filtration rate [GFR], effective renal plasma flow [ERPF], renal vascular resistance [RVR]) in adults with type 1 diabetes (T1D). METHODS The study sample comprised patients with longstanding T1D (duration ≥50 years), among whom 44 were diabetic kidney disease (DKD) resistors (eGFR >60 mL/min/1.73 m2 and

Inflammation participates in the initiation and progression of atherosclerotic cardiovascular disease, and it is a critical inciting factor leading to acute ischemic events. Evidence has shown that certain anti-inflammatory medications used to treat non-atherosclerotic inflammatory diseases reduce cardiovascular events. This article reviews evidence that commonly used anti-inflammatory therapies (colchicine, allopurinol, methotrexate), reduce cardiovascular events. We discuss potential mechanisms of action, efficacy, and safety of these therapies and propose a clinical trials design to investigate their efficacy.

IntroductionInsulin pump access in type 1 diabetes may be inequitable. We studied the association between government funding programs for insulin pumps and rates of insulin pump use and disparities between pump users and non-users.Research design and methodsAdults with type 1 diabetes were identified in the National Diabetes Repository, a primary care electronic medical record database of individuals with diabetes from five Canadian provinces. Proportions of individuals using insulin pumps were compared between provinces with and without pump funding programs. Multivariable logistic regression models were used to estimate the odds of insulin pump use adjusting for confounders. Univariate logistic regression models were used to estimate the odds of insulin pump use according to each predictor, according to pump funding program status.ResultsOf 1559 adults with type 1 diabetes, proportions using insulin pumps were 47.8% (95% CI 45.1% to 50.5%) and 37.7% (95% CI 31.5% to 44.1%) in provinces with and without pump funding programs (p=0.0038). Adjusting for age, sex, HbA1c, income quintile, and rural/urban location, the OR for insulin pump use was 1.45 (1.08–1.94) for provinces with pump funding programs compared with provinces without. Higher income was associated with a greater odds of insulin pump use in provinces with pump funding programs, and rural/urban location was not associated with insulin pump use.ConclusionsInsulin pump use is more common in regions with government funding programs. Further research is required to best understand and comprehensively address persistent income disparities between pump users and non-users despite the availability of reimbursement programs.

OBJECTIVE To assess national differences in diabetes care and quality of life (QOL) between individuals with long-standing type 1 diabetes (≥50 years) in Canada and the U.S. RESEARCH DESIGN AND METHODS Cross-sectional data from identical surveys administered in the Canadian Study of Longevity in Diabetes and the Joslin Medalist Study, collected in 2013–2016 and 2005–2011, respectively, were compared. Laboratory values and ophthalmic examination were completed by clinical care physicians for Canadians and the Joslin Clinic for Americans. Univariate comparisons and multivariable regression for HbA1c, QOL, insulin pump use, and coronary artery disease (CAD) were performed. Nephropathy, CAD, and peripheral arterial disease (PAD) were self-reported; neuropathy was defined by a Michigan Neuropathy Screening Instrument (Questionnaire component) score ≥3, and proliferative retinopathy was documented from ophthalmic examination. QOL was self-reported on an ordinal scale. RESULTS Three hundred sixty-one Canadians and 668 Americans had similar ages (mean 65.78 years [SD 8.67] vs. 66.38 years [7.66], P = 0.27) and durations of diabetes (median 53.00 years [interquartile range 51.00, 58.00] vs. 53.00 years [51.00, 57.00], P = 0.51). Canadians had higher HbA1c (mean 7.53% [SD 1.03] [59 mmol/mol] vs. 7.22% [0.98] [55 mmol/mol], P < 0.0001), lower QOL (36.9% vs. 48.7% with “excellent” QOL, P = 0.0002), and less CAD (29.7% vs. 41.2%, P = 0.0003) and insulin pump use (43.3% vs. 55.6%, P = 0.0002). Other complication rates were similar. Residual differences for Canadians compared with Americans remained after adjustment for age, sex, CAD, PAD, education, and relevant a priori selected variables: 0.28% higher HbA1c (P = 0.0004); and odds ratios of 0.68 (95% CI 0.51, 0.90), 0.46 (0.31, 0.68), and 0.71 (0.52, 0.96) for higher QOL, CAD, and insulin pump use, respectively. CONCLUSIONS Although Canadians and Americans have similar rates of complications other than CAD, further research is required to understand why Canadians have higher HbA1c levels, lower QOL, and less insulin pump use.

Summary Background Closed-loop artificial pancreas systems have been in development for several years, including assessment in numerous varied outpatient clinical trials. We aimed to summarise the efficacy and safety of artificial pancreas systems in outpatient settings and explore the clinical and technical factors that can affect their performance. Methods We did a systematic review and meta-analysis of randomised controlled trials comparing artificial pancreas systems (insulin only or insulin plus glucagon) with conventional pump therapy (continuous subcutaneous insulin infusion [CSII] with blinded continuous glucose monitoring [CGM] or unblinded sensor-augmented pump [SAP] therapy) in adults and children with type 1 diabetes. We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials for studies published from 1946, to Jan 1, 2017. We excluded studies not published in English, those involving pregnant women or participants who were in hospital, and those testing adjunct medications other than glucagon. The primary outcome was the mean difference in percentage of time blood glucose concentration remained in target range (3·9–10 mmol/L or 3·9–8 mmol/L, depending on the study), assessed by random-effects meta-analysis. This study is registered with PROSPERO, number 2015:CRD42015026854. Findings We identified 984 reports; after exclusions, 27 comparisons from 24 studies (23 crossover and one parallel design) including a total of 585 participants (219 in adult studies, 265 in paediatric studies, and 101 in combined studies) were eligible for analysis. Five comparisons assessed dual-hormone (insulin and glucagon), two comparisons assessed both dual-hormone and single-hormone (insulin only), and 20 comparisons assessed single-hormone artificial pancreas systems. Time in target was 12·59% higher with artificial pancreas systems (95% CI 9·02–16·16; p I 2 =84%). Dual-hormone artificial pancreas systems were associated with a greater improvement in time in target range compared with single-hormone systems (19·52% [95% CI 15·12–23·91] vs 11·06% [6·94 to 15·18]; p=0·006), although six of seven comparisons compared dual-hormone systems to CSII with blinded CGM, whereas 21 of 22 single-hormone comparisons had SAP as the comparator. Single-hormone studies had higher heterogeneity than dual-hormone studies ( I 2 79% vs 66%). Bias assessment characteristics were incompletely reported in 12 of 24 studies, no studies masked participants to the intervention assignment, and masking of outcome assessment was not done in 12 studies and was unclear in 12 studies. Interpretation Artificial pancreas systems uniformly improved glucose control in outpatient settings, despite heterogeneous clinical and technical factors. Funding None.

PUA is associated with renin angiotensin aldosterone system (RAAS) activation, which promotes hypertension and kidney disease in T1D. Our aims were to examine (1) the effect of an ANG II infusion on PUA and (2) the association between PUA and systemic and renal hemodynamic responses to ANG II over a wide range of T1D duration. In this post hoc analysis, blood pressure, PUA, GFRinulin and ERPFPAH were measured during a euglycemic clamp before and after an ANG II infusion (1 ng·kg-1·min-1) in participants with T1D: 49 young (26.2±5.5 years) and 62 older (66.0±7.9 years) adults and healthy controls (HC): 27 young (25.1±4.6 years), and 72 older (64.6±8.0 years) adults. ANG II infusion caused a greater decline in GFRinulin in older vs. younger adults with T1D; there was no such difference between older vs. younger HC adults. ANG II decreased PUA more in HC than T1D in both age groups (p Our findings suggest that ANG II infusion reduces PUA, potentially through direct effects on the ANG II type 1 receptor (AT1R). The presence of T1D attenuates PUA lowering effects irrespective of diabetes duration, suggesting an interaction between hyperglycemia, RAAS signaling pathways and PUA. Further studies are required to better understand the effects of AT1R receptor signaling on PUA concentrations. Disclosure Y. Lytvyn: None. J.A. Lovshin: Consultant; Self; Eli Lilly and Company, Intarcia Therapeutics, Inc., Prometic Life Sciences Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. P. Bjornstad: Advisory Panel; Self; Horizon, XORTX. Consultant; Self; Bayer US, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company. L. Lovblom: None. A. Katz: None. A. Lytvyn: None. G. Boulet: Other Relationship; Self; Medtronic. M.A. Farooqi: None. A. Weisman: None. H.A. Keenan: Employee; Self; Sanofi Genzyme. M.H. Brent: Advisory Panel; Self; AbbVie Inc., Bayer Canada, Novartis Canada. Research Support; Self; Bayer Canada, Novartis Canada, Roche Canada. N. Paul: Consultant; Self; Bayer AG. V. Bril: Advisory Panel; Self; Akcea Therapeutics, Alexion Pharmaceuticals, Inc., Alnylam, CSL Behring. Consultant; Self; Pfizer Inc. Research Support; Self; Baxter, Biogen, Grifols, UCB, Inc. A. Advani: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Dexcom, Inc., Novo Nordisk A/S. Research Support; Self; Boehringer Ingelheim International GmbH. B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. Funding JDRF (17-2013-312)

Electronic Medical Record (EMR) data are an efficient method for constructing large type 1 diabetes (T1D) cohorts but are limited by availability of accurate diagnosis codes. We sought to derive an algorithm for identifying T1D using Electronic Medical Records - Primary Care (EMRPC) also known as EMRALD, a database including records from >300,000 primary care patients in Ontario, Canada. A 25% random sample of adults with diabetes and at least 1 year of records in EMRPC prior to September 30, 2015 formed the reference cohort. Charts of potential T1D cases (those on insulin±metformin) were abstracted; all others were classified as non-T1D. Algorithms were derived using variables from free-text searches (diagnosis terms in the Cumulative Patient Profile (CPP)) and standardized fields (medications, age, BMI) using 1)a priori combinations of variables; 2)classification and regression tree analysis (CART). Algorithms were evaluated for sensitivity, specificity, positive and negative predictive values (PPV and NPV) with adjustment for optimism for CART. Of 21,547 eligible patients with diabetes, the reference cohort was 5407: 4968 non-abstracted non-T1D, 240 abstracted non-T1D and 199 T1D. The prevalence of T1D was 3.7%. The optimal algorithm using a priori variable combinations was T1D diagnosis in the CPP + rapid-acting insulin (sensitivity 69.3% (95% CI 62.4-75.7%), specificity 99.8% (99.6-99.9), PPV 92.6% (87.2-96.3), NPV 98.8% (98.5-99.1)). CART partitioned on T1D diagnosis in the CPP, any insulin, and non-metformin oral hypoglycemic medications and improved performance with optimism-adjusted sensitivity of 77% (72.0-83.9), specificity 99.8% (99.8-100.0), PPV 96.8% (94.6-99.6), and NPV 99.1% (98.9-99.4). Simple algorithms using EMR variables yielded good diagnostic performance for identification of T1D and CART further improved performance. Pending additional validation these algorithms can be applied to study large T1D cohorts in EMR databases. Disclosure A. Weisman: None. J. Young: None. M. Kumar: None. P. Austin: None. K. Tu: None. L. Jaakkimainen: None. L. Lipscombe: None. G. Booth: None. Funding Diabetes Action Canada

Objectives To better understand the dawn phenomenon in type 1 diabetes, we sought to determine its prevalence, timing and magnitude in studies specifically designed to assess basal insulin requirements in patients using insulin pumps. Methods Thirty-three participants from 2 sensor-augmented insulin pump studies were analyzed. Twenty participants were obtained from a methodologically ideal semiautomated basal analysis trial in which basal rates were determined from repeated fasting tests (the derivation set) and 13 from an artificial pancreas trial in which duration of fasting was variable (the “confirmation” set). Prevalence was determined for the total cohort and for individual trials using the standard definition of an increase in insulin exceeding 20% and lasting ≥90 minutes. Among cases, time of onset and percent change in the magnitude of basal delivery were determined. Results Seventeen participants (52%) experienced the dawn phenomenon (11 of 20 [55%] in the derivation set and 6 of 13 [46%] in the confirmation set). Time of onset was 3 AM (interquartile range [IQR], 3 to 4:15 AM) in the derivation set and 3 AM (IQR, 3 to 4 AM) in the confirmation set. The magnitude of the dawn phenomenon was a 58.1% (IQR, 28.8% to 110.6%) increase in insulin requirements in the derivation set and 65.5% (IQR, 45.6% to 87.4%) in the confirmation set. Conclusions The dawn phenomenon occurs in approximately half of patients with type 1 diabetes; when present, it has predictable timing of onset (generally 3 AM) and a substantial, but highly variable, magnitude. These findings imply that optimization of glycemic control requires clinical emphasis on fasted overnight basal insulin assessment.

Background There has been growing interest in using administrative and electronic medical record (EMR) data to identify type 1 diabetes (T1D) for clinical and health services research. Our aim was to create an algorithm identifying T1D using EMR data alone and/or in combination with administrative data in Ontario, Canada. Methods The Electronic Medical Record Administrative data Linked Database (EMRALD) was used to create a reference standard for diabetes type as determined by chart abstraction by an endocrinologist. EMRALD contains data from over 350 family physicians using Practice Solutions® EMR. We included patients receiving care from participating physicians who were diagnosed with diabetes prior to Sept 30, 2015. A random 25% sample of patients with diabetes (identified using a validated algorithm) were selected for the reference standard. Patients who were not prescribed insulin or who were prescribed insulin and an oral hypoglycemic agent other than metformin were automatically classified as not having T1D without chart abstraction. Remaining patients underwent chart abstraction to determine diabetes type. 50 charts were randomly re-abstracted for inter- and intra-rater reliability. Characteristics of patients by diabetes type were reviewed to select variables for algorithm inclusion. Preliminary Results There were 23,310 patients with diabetes as of September 30, 2015. The reference standard consisted of 5828 patients: 5305 were classified as not T1D without chart abstraction and 523 underwent chart abstraction. Inter- and intra-rater reliability were high (Cohen’s kappa 0.82 and 0.96, respectively). After chart abstraction,14 patients were classified as not having diabetes, 233 patients were classified as T1D (45.8%), 261 as not T1D (51.3%), and 15 as possible T1D (2.9%). The prevalence of T1D was 4.0%. Compared to 5581 patients without definite T1D, patients with T1D were younger (median 40 years [IQR 30-53] v. 66[57-75]), had a younger age of onset (15 years [10-25] v. 47[40-55]), and a lower body mass index (BMI) (26±5 v. 32±8). Age at diagnosis and BMI were documented in 349(71.8%) of abstracted charts and 1386(23.8%), respectively. Renal insufficiency (eGFR

We aimed to determine cross-sectional insulin pump prevalence and factors associated with measures of glycemic control as a secondary analysis in a long-standing type 1 diabetes mellitus (T1DM) national cohort.Canadian participants with ≥50 years of T1DM (n = 305) were administered a comprehensive mail-based questionnaire including acquisition of contemporaneous laboratory results. Factors associated with pump use, glycosylated hemoglobin (HbA1c), and hypoglycemia were analyzed by regression.The 305 participants had a median age of 65 [interquartile range, 59, 71] years, median diabetes duration of 54 [51, 59] years, and mean HbA1c level of 7.5 ± 1.1%. Prevalence of pump use was 44% (133/305), with median duration of use 8 [4, 13] years. Compared with the non-pump subgroup, the pump subgroup had numerically lower but similar HbA1c levels (7.4 ± 0.9% vs. 7.6 ± 1.2%; P = 0.22) and reported greater numbers of minor hypoglycemia events (6.5 vs. 5.1 events/patient·month; P = 0.004) and fewer severe hypoglycemia events (0.5 vs. 1.3 events/patient·year; P = 0.02) in the past year. More frequent daily glucose tests and more frequent minor hypoglycemia events-but not pump therapy or its prescription parameters-were independently associated with lower HbA1c level in multivariable regression. However, use of insulin pump and habitual use of continuous glucose monitoring (≥1 week/month) were each independently associated with lower risk of severe hypoglycemia (risk ratio = 0.50 [P 0.0001] and 0.30 [P = 0.001], respectively).Insulin pump and continuous glucose monitoring technologies were associated with lower risk of severe hypoglycemia, while frequent daily glucose testing was associated with lower HbA1c level. These findings imply that basic self-management skill and technology play complementary roles in glycemic control among older adults with long-standing T1DM.