Associations between Allopurinol and Cardiovascular and Renal Outcomes in Diabetes

Diabetes is a leading cause of cardiovascular and kidney disease, and novel therapies to reduce these adverse diabetes outcomes are urgently required. Allopurinol, a uric acid-lowering therapy traditionally used for the treatment of gout, may reduce mortality and cardiovascular and kidney disease through reductions in oxidative stress and improved endothelial function, but this has not been well-studied in diabetes. Through three related projects, this thesis examines the associations between allopurinol and all-cause mortality, cardiovascular and renal outcomes in individuals with diabetes using population-based administrative health care data in Ontario, Canada. The first project examined patterns of allopurinol use and their predictors, to inform the design of subsequent studies. In 38,416 individuals with diabetes newly prescribed allopurinol, discontinuation and interruption of allopurinol were common. Female sex and greater severity of gout were associated with worse adherence. The second project evaluated the association between allopurinol-exposed time and all-cause mortality and cardiovascular outcomes in 38,416 new allopurinol users with diabetes. Allopurinol-exposed time was associated with a reduced risk of the primary composite outcome of all-cause mortality, atherothrombotic cardiovascular events (myocardial infarction, revascularization, stroke), or heart failure, which was primarily driven by a reduction in all-cause mortality. However, healthy user bias could not be completely excluded. The third project evaluated the association between allopurinol use and progression of chronic kidney disease (CKD) or development of end-stage renal disease (ESRD). In 5937 individuals with a gout flare and Stages 1 to 3 CKD at baseline (1911 with diabetes), renal outcomes did not differ between allopurinol users and non-users after weighting by the inverse probability of treatment. Based on the thesis results, allopurinol may reduce mortality and atherothrombotic cardiovascular events in individuals with diabetes, but does not appear to reduce heart failure, CKD progression, or development of ESRD. Defining allopurinol exposure in pharmacoepidemiology studies is challenging due to frequent interruptions and discontinuation. Thus, study designs incorporating time-varying exposure and time-varying confounders may be more robust. A clinical trial designed to evaluate the effect of allopurinol on atherothrombotic cardiovascular events in individuals with diabetes and hyperuricemia is strongly justified.Ph.D

Whipple’s Endocarditis: An Enigmatic Cause of Culture-Negative Bacterial Endocarditis

Peer Reviewe

Validation of a type 1 diabetes algorithm using electronic medical records and administrative healthcare data to study the population incidence and prevalence of type 1 diabetes in Ontario, Canada

Introduction We 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 methods The 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.Results Of 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, p<0.0001). In contrast, incidence rates decreased (minimum estimate 0.1 to 0.04, maximum estimate 0.47 to 0.09, p<0.0001).Conclusions Primary 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

Identification and prediction of diabetic sensorimotor polyneuropathy using individual and simple combinations of nerve conduction study parameters.

OBJECTIVE: Evaluation of diabetic sensorimotor polyneuropathy (DSP) is hindered by the need for complex nerve conduction study (NCS) protocols and lack of predictive biomarkers. We aimed to determine the performance of single and simple combinations of NCS parameters for identification and future prediction of DSP. MATERIALS AND METHODS: 406 participants (61 with type 1 diabetes and 345 with type 2 diabetes) with a broad spectrum of neuropathy, from none to severe, underwent NCS to determine presence or absence of DSP for cross-sectional (concurrent validity) analysis. The 109 participants without baseline DSP were re-evaluated for its future onset (predictive validity). Performance of NCS parameters was compared by area under the receiver operating characteristic curve (AROC). RESULTS: At baseline there were 246 (60%) Prevalent Cases. After 3.9 years mean follow-up, 25 (23%) of the 109 Prevalent Controls that were followed became Incident DSP Cases. Threshold values for peroneal conduction velocity and sural amplitude potential best identified Prevalent Cases (AROC 0.90 and 0.83, sensitivity 80 and 83%, specificity 89 and 72%, respectively). Baseline tibial F-wave latency, peroneal conduction velocity and the sum of three lower limb nerve conduction velocities (sural, peroneal, and tibial) best predicted 4-year incidence (AROC 0.79, 0.79, and 0.85; sensitivity 79, 70, and 81%; specificity 63, 74 and 77%, respectively). DISCUSSION: Individual NCS parameters or their simple combinations are valid measures for identification and future prediction of DSP. Further research into the predictive roles of tibial F-wave latencies, peroneal conduction velocity, and sum of conduction velocities as markers of incipient nerve injury is needed to risk-stratify individuals for clinical and research protocols

Growing income-related disparities in cardiovascular hospitalizations among people with diabetes, 1995 to 2019: population-based study

   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. </p

Concurrent validity ROC curves for sural, peroneal, tibial and summative parameters.

<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058783#pone-0058783-t002" target="_blank">Table 2</a> for estimates of AROC for each parameter. Peroneal conduction velocity and sural amplitude potential had the highest AROC (AROC 0.90 and 0.83, respectively). Dashed lines represent amplitude potentials. Solid lines represent conduction velocities. Dotted lines represent F-wave latencies.</p

Baseline Characteristics of the 251 Prevalent DSP Cases and the 107 Prevalent Controls According to the 4-Year Incidence of DSP.

<p>Data are means ± standard deviations or <i>n</i> (%). For comparisons between two groups, p values reported are χ² test statistics for categorical variables and T-tests for continuous variables. For comparisons between three groups, p values reported are χ² test statistics for categorical variables and ANOVA for continuous variables. Normal values for individual NCS are as follows. Sural amp≥7.2 µV for age ≤65 and ≥5.5 µV for age >65, sural CV≥40 m/s, peroneal amp≥5 µV for age ≤65 and ≥3 for age >65, peroneal CV≥40 m/s, peroneal F wave ≤59 ms for height ≥182.9 cm and ≤58 ms for height ≤182.9 cm, tibial amp≥10 µV, tibial CV≥40 m/s, tibial F wave ≤55 ms.</p>*<p>p-value for ANOVA between Prevalent Cases, Incident DSP Cases and Incident DSP Controls.</p>†<p>By subject self-report.</p>‡<p>HbA1C, glycated hemoglobin A1C.</p>§<p>Summative parameters are composed of the following: sum amplitude = sural+tibial, sum conduction velocity = sural+peroneal +tibial, sum F-wave latency = peroneal+tibial.</p>¶<p>Summed amplitude potentials are expressed in arbitrary units since sural amplitude potential is measured in microvolts and tibial amplitude potential is measured in millivolts.</p>∥<p>Statistical tests for the NCS parameters applied a Bonferroni correction for multiple comparisons for significance such that p-values <0.0045 (0.05/11) were considered significant. All p-values except for two indicated by this symbol, met significance criteria.</p><p> <b>TCNS, Toronto Clinical Neuropathy Score. Amp, amplitude potential. CV, conduction velocity. F-wave, F-wave latency.</b></p

Comparison of Area Under the Receiver Operating Characteristic Curve (AROC) Between Individual and Summative NCS Parameters for the Cross-Cectional (Concurrent Validity) Analysis and the Longitudinal (Predictive Validity) Analysis.

<p>Normal values for individual NCS are as follows. Sural amp≥7.2 µV for age ≤65 and ≥5.5 µV for age >65, sural CV≥40 m/s, peroneal amp≥5 µV for age ≤65 and ≥3 for age >65, peroneal CV≥40 m/s, peroneal F wave ≤59 ms for height ≥182.9 cm and ≤58 ms for height ≤182.9 cm, tibial amp≥10 µV, tibial CV≥40 m/s, tibial F wave ≤55 ms.</p>*<p>Two tailed p value for comparison with the AROC for the parameters with the highest AROC in concurrent and predictive analyses.</p>†<p>Established by the distribution in healthy control subects <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058783#pone.0058783-Oh1" target="_blank">[23]</a>.</p>‡<p>Summative parameters are composed of the following: sum amplitude = sural+tibial, sum conduction velocity = sural+peroneal +tibial, sum F-wave latency = peroneal+tibial. Summed amplitude potentials are expressed in arbitrary units since sural amplitude potential is measured in microvolts and tibial amplitude potential is measured in millivolts.</p><p> <b>Amp, amplitude potential. CV, conduction velocity. F-wave, F-wave latency.</b></p