Preexisting Diabetes Mellitus and All-Cause Mortality in Adult Patients With Sepsis: A Population-Based Cohort Study.

OBJECTIVES: We assessed the association of preexisting diabetes mellitus with all-cause mortality and organ support receipt in adult patients with sepsis. DESIGN: Population-based cohort study. SETTING: Ontario, Canada (2008-2019). POPULATION: Adult patients (18 yr old or older) with a first sepsis-related hospitalization episode. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The main exposure of interest was preexisting diabetes (either type 1 or 2). The primary outcome was all-cause mortality by 90 days; secondary outcomes included receipt of invasive mechanical ventilation and new renal replacement therapy. We report adjusted (for baseline characteristics using standardization) risk ratios (RRs) alongside 95% CIs. A main secondary analysis evaluated the potential mediation by prior metformin use of the association between preexisting diabetes and all-cause mortality following sepsis. Overall, 503,455 adults with a first sepsis-related hospitalization episode were included; 36% had preexisting diabetes. Mean age was 73 years, and 54% of the cohort were females. Preexisting diabetes was associated with a lower adjusted risk of all-cause mortality at 90 days (RR, 0.81; 95% CI, 0.80-0.82). Preexisting diabetes was associated with an increased risk of new renal replacement therapy (RR, 1.53; 95% CI, 1.46-1.60) but not invasive mechanical ventilation (RR, 1.03; 95% CI, 1.00-1.05). Overall, 21% (95% CI, 19-28) of the association between preexisting diabetes and reduced risk of all-cause mortality was mediated by prior metformin use. CONCLUSIONS: Preexisting diabetes is associated with a lower risk of all-cause mortality and higher risk of new renal replacement therapy among adult patients with sepsis. Future studies should evaluate the underlying mechanisms of these associations.

An assessment of adaptation and fidelity in the implementation of an audit and feedback-based intervention to improve transition to adult type 1 diabetes care in Ontario, Canada.

BACKGROUND: The fit between an intervention and its local context may affect its implementation and effectiveness. Researchers have stated that both fidelity (the degree to which an intervention is delivered, enacted, and received as intended) and adaptation to the local context are necessary for high-quality implementation. This study describes the implementation of an audit and feedback (AF)-based intervention to improve transition to type 1 diabetes adult care, at five sites, in terms of adaptation and fidelity. METHODS: An audit and feedback (AF)-based intervention for healthcare teams to improve transition to adult care for patients with type 1 diabetes was studied at five pediatric sites. The Framework for Reporting Adaptations and Modifications to Evidence-based Implementation Strategies (FRAME-IS) was used to document the adaptations made during the study. Fidelity was determined on three different levels: delivery, enactment, and receipt. RESULTS: Fidelity of delivery, receipt, and enactment were preserved during the implementation of the intervention. Of the five sites, three changed their chosen quality improvement initiative, however, within the parameters of the study protocol; therefore, fidelity was preserved while still enabling participants to adapt accordingly. CONCLUSIONS: We describe implementing a multi-center AF-based intervention across five sites in Ontario to improve the transition from pediatric to adult diabetes care for youth with type 1 diabetes. This intervention adopted a balanced approach considering both adaptation and fidelity to foster a community of practice to facilitate implementing quality improvement initiatives for improving transition to adult diabetes care. This approach may be adapted for improving transition care for youth with other chronic conditions and to other complex AF-based interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03781973. Registered 13 December 2018. Date of enrolment of the first participant to the trial: June 1, 2019.

Determinants, Prevention, and Incidence of Cardiovascular Disease Among Immigrant and Refugee Populations.

Immigration policies shape the composition, socioeconomic characteristics, and health of migrant populations. The health of migrants is also influenced by a confluence of social, economic, environmental, and political factors. Immigrants and refugees often face various barriers to accessing health care because of factors such as lack of familiarity with navigating the health care system, language barriers, systemic racism, and gaps in health insurance. Social determinants of health and access to primary care health services likely influence the burden of cardiovascular risk factors among immigrants. The relatively low burden of many cardiovascular risk factors in many immigrant populations likely contributes to the generally lower incidence rates of acute myocardial infarction, heart failure, and stroke in immigrants compared with nonimmigrants, although cardiovascular disease incidence rates vary substantially by country of origin. The "healthy immigrant effect" is the hypothesis that immigrants to high-income countries, such as Canada, are healthier than nonimmigrants in the host population. However, this effect may not apply universally across all immigrants, including recent refugees, immigrants without formal education, and unmarried immigrants. As unfolding sociopolitical events generate new waves of global migration, policymakers and health care providers need to focus on addressing social and structural determinants of health to better manage cardiovascular risk factors and prevent cardiovascular disease, especially among the most marginalized immigrants and refugees.

Association Between Age at Diagnosis of Type 2 Diabetes and Hospitalization for Heart Failure: A Population-Based Study.

BACKGROUND: The relation between age at diagnosis of type 2 diabetes (T2D) and hospitalization for heart failure (HHF) is unclear. We assessed the association between age at diagnosis of T2D and HHF. METHODS AND RESULTS: We conducted a population-based cohort study using administrative health databases from the Canadian province of Ontario, including participants without prior heart failure. We identified people with new-onset T2D between April 1, 2005 and March 31, 2015, and matched each person with 3 diabetes-free adults, according to birth year and sex. We estimated adjusted hazard ratios (HRs) and rate ratios (RRs) for the association between age at T2D diagnosis and incident HHF, which was assessed until March 31, 2020. Among 743 053 individuals with T2D and 2 199 539 matched individuals without T2D, 126 241 incident HHF events occurred over 8.9 years. T2D was associated with a greater adjusted hazard of HHF at younger ages (eg, HR at age 30 years: 6.94 [95% CI, 6.54-7.36]) than at older ages (eg, HR at age 60 years: 2.50 [95% CI, 2.45-2.56]) relative to matched individuals. Additional adjustment for mediators (hypertension, coronary artery disease, and chronic kidney disease) marginally attenuated this relationship. Age at T2D diagnosis was associated with a greater number of HHF events relative to matched individuals at younger ages (eg, RR at age 30 years: 6.39 [95% CI, 5.76-7.08]) than at older ages (eg, RR at age 60 years: 2.65 [95% CI, 2.54-2.76]). CONCLUSIONS: Younger age at T2D diagnosis is associated with a disproportionately elevated HHF risk relative to age-matched individuals without T2D.

Gestational diabetes in twin pregnancies-a pathology requiring treatment or a benign physiological adaptation?

There is level-1 evidence that screening for and treating gestational diabetes in singleton pregnancies reduce maternal and neonatal morbidity. However, similar data for gestational diabetes in twin pregnancies are currently lacking. Consequently, the current approach for the diagnosis and management of gestational diabetes in twin pregnancies is based on the same diagnostic criteria and glycemic targets used in singleton pregnancies. However, twin pregnancies have unique physiological characteristics, and many of the typical gestational diabetes-related complications are less relevant for twin pregnancies. These differences raise the question of whether the greater increase in insulin resistance observed in twin pregnancies (which is often diagnosed as diet-treated gestational diabetes) should be considered physiological and potentially beneficial in which case alternative criteria should be used for the diagnosis of gestational diabetes in twin pregnancies. In this review, we summarize the most up-to-date evidence on the epidemiology, pathophysiology, and clinical consequences of gestational diabetes in twin pregnancies and review the available data on twin-specific screening and diagnostic criteria for gestational diabetes. Although twin pregnancies are associated with a higher incidence of diet-treated gestational diabetes, diet-treated gestational diabetes in twin pregnancies is less likely to be associated with adverse outcomes and accelerated fetal growth than in singleton pregnancies and may reduce the risk for intrauterine growth restriction. In addition, there is currently no evidence that treatment of diet-treated gestational diabetes in twin pregnancies improves outcomes, whereas preliminary data suggest that strict glycemic control in such cases might increase the risk for intrauterine growth restriction. Overall, these findings provide support to the hypothesis that the greater transient increase in insulin resistance observed in twin pregnancies is merely a physiological exaggeration of the normal increase in insulin resistance observed in singleton pregnancies (that is meant to support 2 fetuses) rather than a pathology that requires treatment. These data illustrate the need to develop twin-specific screening and diagnostic criteria for gestational diabetes to avoid overdiagnosis of gestational diabetes and to reduce the risks associated with overtreatment of diet-treated gestational diabetes in twin pregnancies. Although data on twin-specific screening and diagnostic criteria are presently scarce, preliminary data suggest that the optimal screening and diagnostic criteria in twin pregnancies are higher than those currently used in singleton pregnancies.

The Impact of Blood Glucose Test Strips Reimbursement Limits on Utilization, Costs, and Health-care Utilization in British Columbia.

OBJECTIVE: People living with diabetes and not using insulin may not derive clinically significant benefit from routine glucose self-monitoring. As a result, in 2015, British Columbia (BC) introduced quantity restrictions for blood glucose test strips (BGTS) coverage in public plans. We studied the impact of this policy on utilization, costs, and health-care utilization. METHODS: We identified a cohort of adults (≥18 years old) with diabetes between 2013 and 2019. Using BC's administrative data, we studied utilization and costs among individuals with at least one PharmaCare-eligible BGTS claim. Using interrupted time-series analysis, we studied cost savings and determined the level of policy adherence. In addition, we investigated longitudinal changes in all-cause and diabetes-specific physician visits, all-cause hospitalizations, and health-care spending in the 3 to 5 years after policy implementation. RESULTS: Over the study period, 279.7 million BGTS were eligible for PharmaCare coverage, on which the government spent $124.3 million. After policy implementation, we observed an immediate decline in average utilization and PharmaCare expenditure on BGTS, leading to an estimated $44.6 million in savings between 2015 and 2019 (95% confidence interval $16.9 to $72.3 million). We found no association between the policy's implementation and health services utilization or overall health-care spending over the long term. CONCLUSIONS: Restricting reimbursement for BGTS in BC resulted in significant cost savings without any attendant increase in health services utilization over the subsequent 5 years. This disinvestment freed up resources that could be channeled toward other interventions.

No association between metformin initiation and incident dementia in older adults newly diagnosed with diabetes.

BACKGROUND: Metformin has been suggested to reduce dementia risk; however, most epidemiologic studies have been limited by immortal time bias or confounding due to disease severity. OBJECTIVES: To investigate the association of metformin initiation with incident dementia using strategies that mitigate these important sources of bias. METHODS: Residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered this retrospective population-based cohort. To consider the indication for metformin monotherapy initiation, people with hemoglobin A1c of 6.5%-8.0% and estimated glomerular filtration rate ≥45 mL/min/1.73 m2 were selected. Using the landmark method to address immortal time bias, exposure was grouped into "metformin monotherapy initiation within 180 days after new diabetes diagnosis" or "no glucose-lowering medications within 180 days." To address disease latency, 1-year lag time was applied to the end of the 180-day landmark period. Incident dementia was defined using a validated algorithm for Alzheimer's disease and related dementias. Adjusted hazard ratios (aHR) and confidence intervals (CIs) were estimated from propensity-score weighted Cox proportional hazard models. RESULTS: Over mean follow-up of 6.77 years from cohort entry, metformin initiation within 180 days after new diabetes diagnosis (N = 12,331; 978 events; 65,762 person-years) showed no association with dementia risk (aHR [95% CI] = 1.05 [0.96-1.15]), compared to delayed or no glucose-lowering medication initiation (N = 22,369; 1768 events; 117,415 person-years). CONCLUSION: Early metformin initiation was not associated with incident dementia in older adults newly diagnosed with diabetes. The utility of metformin to prevent dementia was not supported.

Risk Prediction Scores for Type 2 Diabetes Microvascular and Cardiovascular Complications Derived and Validated With Real-world Data From 2 Provinces: The DIabeteS COmplications (DISCO) Risk Scores.

OBJECTIVES: Existing tools to predict the risk of complications among people with type 2 diabetes poorly discriminate high- from low-risk patients. Our aim in this study was to develop risk prediction scores for major type 2 diabetes complications using real-world clinical care data, and to externally validate these risk scores in a different jurisdiction. METHODS: Using health-care administrative data and electronic medical records data, risk scores were derived using data from 25,088 people with type 2 diabetes from the Canadian province of Ontario, followed between 2002 and 2017. Scores were developed for major clinically important microvascular events (treatment for retinopathy, foot ulcer, incident end-stage renal disease), cardiovascular disease events (acute myocardial infarction, heart failure, stroke, amputation), and mortality (cardiovascular, noncardiovascular, all-cause). They were then externally validated using the independent data of 11,416 people with type 2 diabetes from the province of Manitoba. RESULTS: The 10 derived risk scores had moderate to excellent discrimination in the independent validation cohort, ranging from 0.705 to 0.977. Their calibration to predict 5-year risk was excellent across most levels of predicted risk, albeit with some displaying underestimation at the highest levels of predicted risk. CONCLUSIONS: The DIabeteS COmplications (DISCO) risk scores for major type 2 diabetes complications were derived and externally validated using contemporary real-world clinical data. As a result, they may be more accurate than other risk prediction scores derived using randomized trial data. The use of more accurate risk scores in clinical practice will help improve personalization of clinical care for patients with type 2 diabetes.

Risk of Breast Cancer After Diabetes in Pregnancy: A Population-based Cohort Study.

OBJECTIVES: Diabetes is associated with an increased risk of several cancers, including postmenopausal breast cancer. The evidence for higher breast cancer risk after diabetes in pregnancy is conflicting. We compared the incidence of breast and other cancers between pregnant women with and without diabetes. METHODS: This work was a propensity-matched, retrospective cohort study using population-based health-care databases from Ontario, Canada. Those deliveries with gestational diabetes mellitus (GDM) and pregestational diabetes mellitus (pregestational DM) were identified and matched to deliveries without diabetes mellitus (non-DM). Deliveries from each diabetes cohort were matched 1:2 on age, parity, year of delivery, and propensity score to non-DM deliveries. Matched subjects were followed from delivery for incidence of breast cancer as a primary outcome, and other site-specific cancers as secondary outcomes. We performed Cox proportional hazards regression to compare rates of breast cancer between matched groups. RESULTS: Over a median of 8 (interquartile range 4 to 13) years of follow-up, compared with non-DM deliveries, the incidence of breast cancer was significantly lower for GDM but similar for pregestational DM deliveries (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.82 to 0.98; and HR 0.92, 95% CI 0.80 to 1.07, respectively). GDM was associated with a significantly higher incidence of pancreatic and hepatocellular cancer, and pregestational DM was associated with a higher incidence of thyroid, hepatocellular, and endometrial cancers. CONCLUSIONS: Diabetes in pregnancy does not have a higher short-term risk of subsequent breast cancer, but there may be a higher incidence of other cancers.

Ethnic differences in the association between age at diagnosis of diabetes and the risk of cardiovascular complications: a population-based cohort study.

BACKGROUND: We examined ethnic differences in the association between age at diagnosis of diabetes and the risk of cardiovascular complications. METHODS: We conducted a population-based cohort study in Ontario, Canada among individuals with diabetes and matched individuals without diabetes (2002-18). We fit Cox proportional hazards models to determine the associations of age at diagnosis and ethnicity (Chinese, South Asian, general population) with cardiovascular complications. We tested for an interaction between age at diagnosis and ethnicity. RESULTS: There were 453,433 individuals with diabetes (49.7% women) and 453,433 matches. There was a significant interaction between age at diagnosis and ethnicity (P < 0.0001). Young-onset diabetes (age at diagnosis < 40) was associated with higher cardiovascular risk [hazard ratios: Chinese 4.25 (3.05-5.91), South Asian: 3.82 (3.19-4.57), General: 3.46 (3.26-3.66)] than usual-onset diabetes [age at diagnosis ≥ 40 years; Chinese: 2.22 (2.04-2.66), South Asian: 2.43 (2.22-2.66), General: 1.83 (1.81-1.86)] versus ethnicity-matched individuals. Among those with young-onset diabetes, Chinese ethnicity was associated with lower overall cardiovascular [0.44 (0.32-0.61)] but similar stroke risks versus the general population; while South Asian ethnicity was associated with lower overall cardiovascular [0.75 (0.64-0.89)] but similar coronary artery disease risks versus the general population. In usual-onset diabetes, Chinese ethnicity was associated with lower cardiovascular risk [0.44 (0.42-0.46)], while South Asian ethnicity was associated with lower cardiovascular [0.90 (0.86-0.95)] and higher coronary artery disease [1.08 (1.01-1.15)] risks versus the general population. CONCLUSIONS: There are important ethnic differences in the association between age at diagnosis and risk of cardiovascular complications.

Post-initiation predictors of discontinuation of the sodium-glucose cotransporter-2 inhibitors: A comparative cohort study from the United Kingdom.

AIMS: To assess post-initiation predictors of discontinuation of sodium-glucose cotransporter-2 (SGLT2) inhibitors compared to dipeptidyl-peptidase-4 (DPP-4) inhibitors in the United Kingdom. MATERIALS AND METHODS: We conducted a comparative population-based retrospective cohort study using primary care data from the UK Clinical Practice Research Datalink (CPRD) with linked data to hospital and death records. We included new metformin users who initiated either SGLT2 inhibitors or DPP-4 inhibitors between January 2013 and October 2019. The main outcome was treatment discontinuation, defined as the first 90-day gap after the estimated treatment end date. We used a series of extended Cox models to assess which time-dependent predictors were associated with treatment discontinuation. To test if the hazard ratio of discontinuation for each predictor was statistically different between SGLT2 and DPP-4 inhibitors, an exposure-predictor interaction term was added to each model. RESULTS: There were 2550 new users of SGLT2 inhibitors and 8195 new users of DPP-4 inhibitors. Approximately 69% of SGLT2 inhibitor and 74% of DPP-4 inhibitor users had discontinued treatment by the end of follow-up. Occurrence of fractures after treatment initiation was a significant predictor of discontinuation of SGLT2 inhibitors (hazard ratio [HR] 4.13, 95% confidence interval [CI] 2.12-8.06) but not DPP-4 inhibitors (HR 0.93, 95% CI 0.79-1.11). The rate of treatment discontinuation was significantly higher for those with low estimated glomerular filtration rate and minimal contact with the healthcare system. Efficacy endpoints, such as heart failure and glycated haemoglobin level, were not associated with treatment discontinuation. CONCLUSIONS: Our findings reflect some discrepancy between the available evidence and prescribing behaviour for SGLT2 inhibitors.

Association of prior outpatient diabetes screening with cardiovascular events and mortality among people with incident diabetes: a population-based cohort study.

BACKGROUND: Outcomes of diabetes screening in contemporary, multi-ethnic populations are unknown. We examined the association of prior outpatient diabetes screening with the risks of cardiovascular events and mortality in Ontario, Canada. METHODS: We conducted a population-based cohort study using administrative databases among adults aged ≥ 20 years with incident diabetes diagnosed during 2014-2016. The exposure was outpatient diabetes screening performed within 3 years prior to diabetes diagnosis. The co-primary outcomes were (1) a composite of all-cause mortality and hospitalization for myocardial infarction, stroke, coronary revascularization, and (2) all-cause mortality (followed up until 2018). We calculated standardized rates of each outcome and conducted cause-specific hazard modelling to determine the adjusted hazard ratio (HR) of the outcomes, adjusting for prespecified confounders and accounting for the competing risk of death. RESULTS: We included 178,753 Ontarians with incident diabetes (70.2% previously screened). Individuals receiving prior screening were older (58.3 versus 53.4 years) and more likely to be women (49.6% versus 40.0%) than previously unscreened individuals. Individuals receiving prior screening had relatively lower standardized event rates than those without prior screening across all outcomes (composite: 12.8 versus 18.1, mortality: 8.2 versus 11.1 per 1000 patient-years). After multivariable adjustment, prior screening was associated with 34% and 32% lower risks of the composite (HR 0.66, 0.63-0.69) and mortality (0.68, 0.64-0.72) outcomes. Among those receiving prior screening, a result in the prediabetes range was associated with lower risks of the composite (0.82, 0.77-0.88) and mortality (0.71, 0.66-0.78) outcomes than a result in the normoglycemic range. CONCLUSIONS: Previously screened individuals with diabetes had lower risks of cardiovascular events and mortality versus previously unscreened individuals. Better risk assessment tools are needed to support wider and more appropriate uptake of diabetes screening, especially among young adults.

Glycemic control and neonatal outcomes in twin pregnancies with gestational diabetes mellitus.

BACKGROUND: Preliminary data suggest that strict glycemic control in twin pregnancies with gestational diabetes mellitus may not improve outcomes but might increase the risk of fetal growth restriction. OBJECTIVE: This study aimed to investigate the association of maternal glycemic control with the risk of gestational diabetes mellitus-related complications and small for gestational age in twin pregnancies complicated by gestational diabetes mellitus. STUDY DESIGN: This was a retrospective cohort study of all patients with a twin pregnancy complicated by gestational diabetes mellitus in a single tertiary center between 2011 and 2020, and a matched control group of patients with a twin pregnancy without gestational diabetes mellitus in a 1:3 ratio. The exposure was the level of glycemic control, described as the proportion of fasting, postprandial, and overall glucose values within target. Good glycemic control was defined as a proportion of values within target above the 50th percentile. The first coprimary outcome was a composite variable of neonatal morbidity, defined as at least 1 of the following: birthweight >90th centile for gestational age, hypoglycemia requiring treatment, jaundice requiring phototherapy, birth trauma, or admission to the neonatal intensive care unit at term. A second coprimary outcome was small for gestational age, defined as birthweight <10th centile or <3rd centile for gestational age. Associations between the level of glycemic control and the study outcomes were estimated using logistic regression analysis and were expressed as adjusted odds ratio with 95% confidence interval. RESULTS: A total of 105 patients with gestational diabetes mellitus in a twin pregnancy met the study criteria. The overall rate of the primary outcome was 32.4% (34/105), and the overall proportion of pregnancies with a small for gestational age newborn at birth was 43.8% (46/105). Good glycemic control was not associated with a reduction in the risk of composite neonatal morbidity when compared with suboptimal glycemic control (32.1% vs 32.7%; adjusted odds ratio, 2.06 [95% confidence interval, 0.77-5.49]). However, good glycemic control was associated with higher odds of small for gestational age compared with nongestational diabetes mellitus pregnancies, especially in the subgroup of diet-treated gestational diabetes mellitus (65.5% vs 34.0%, respectively; adjusted odds ratio, 4.17 [95% confidence interval, 1.74-10.01] for small for gestational age <10th centile; and 24.1% vs 7.0%, respectively; adjusted odds ratio, 3.97 [95% confidence interval, 1.42-11.10] for small for gestational age <3rd centile). In contrast, the rate of small for gestational age in gestational diabetes mellitus pregnancies with suboptimal control was not considerably different when compared with non-gestational diabetes mellitus pregnancies. In addition, in cases of diet-treated gestational diabetes mellitus, good glycemic control was associated with a left-shift of the distribution of birthweight centiles, whereas the distribution of birthweight centiles among gestational diabetes mellitus pregnancies with suboptimal control was similar to that of nongestational diabetes mellitus pregnancies. CONCLUSION: In patients with gestational diabetes mellitus in a twin pregnancy, good glycemic control is not associated with a reduction in the risk of gestational diabetes mellitus-related complications but may increase the risk of a small for gestational age newborn in the subgroup of patients with mild (diet-treated) gestational diabetes mellitus. These findings further question whether the gestational diabetes mellitus glycemic targets used in singleton pregnancies also apply to twin pregnancies and support the concern that applying the same diagnostic criteria and glycemic targets in twin pregnancies may result in overdiagnosis and overtreatment of gestational diabetes mellitus and potential neonatal harm.

Prevalent diabetes and long-term cardiovascular outcomes in adult sepsis survivors: a population-based cohort study.

BACKGROUND: Sepsis survivors are at elevated risk for cardiovascular disease during long-term follow-up. Whether diabetes influences cardiovascular risk after sepsis survival remains unknown. We sought to describe the association of diabetes with long-term cardiovascular outcomes in adult sepsis survivors. METHODS: Population-based cohort study in the province of Ontario, Canada (2008-2017). Adult survivors of a first sepsis-associated hospitalization, without pre-existing cardiovascular disease, were included. Main exposure was pre-existing diabetes (any type). The primary outcome was the composite of myocardial infarction, stroke, and cardiovascular death. Patients were followed up to 5 years from discharge date until outcome occurrence or end of study period (March 2018). We used propensity score matching (i.e., 1:1 to patients with sepsis but no pre-existing diabetes) to adjust for measured confounding at baseline. Cause-specific Cox proportional hazards models with robust standard errors were used to estimate hazard ratios (HR) alongside 95% confidence intervals (CI). A main secondary analysis evaluated the modification of the association between sepsis and cardiovascular disease by pre-existing diabetes. RESULTS: 78,638 patients with pre-existing diabetes who had a sepsis-associated hospitalization were matched to patients hospitalized for sepsis but without diabetes. Mean age of patients was 71 years, and 55% were female. Median duration from diabetes diagnosis was 9.8 years; mean HbA1c was 7.1%. Adult sepsis survivors with pre-existing diabetes experienced a higher hazard of major cardiovascular disease (HR 1.25; 95% CI 1.22-1.29)-including myocardial infarction (HR 1.40; 95% CI 1.34-1.47) and stroke (HR 1.24; 95% CI 1.18-1.29)-during long-term follow-up compared to sepsis survivors without diabetes. Pre-existing diabetes modified the association between sepsis and cardiovascular disease (risk difference: 2.3%; 95% CI 2.0-2.6 and risk difference: 1.8%; 95% CI 1.6-2.0 for the effect of sepsis-compared to no sepsis-among patients with and without diabetes, respectively). CONCLUSIONS: Sepsis survivors with pre-existing diabetes experience a higher long-term hazard of major cardiovascular events when compared to sepsis survivors without diabetes. Compared to patients without sepsis, the absolute risk increase of cardiovascular events after sepsis is higher in patients with diabetes (i.e., diabetes intensified the higher cardiovascular risk induced by sepsis).

Incidence of Heart Failure Related to Co-Occurrence of Gestational Hypertensive Disorders and Gestational Diabetes.

BACKGROUND: The extent to which their co-occurrence of gestational hypertensive disorders (GHTD) and gestational diabetes mellitus (GDM) influences heart failure (HF) risk is unclear. OBJECTIVES: The purpose of this study was to characterize the risk of HF related to concomitant GHTD and GDM. METHODS: We conducted a population-based cohort study using the Ministry of Health and Long-Term Care of Ontario (Canada) health care administrative databases. We included women with a livebirth singleton delivery between July 1, 2007, and March 31, 2018, and excluded those with prepregnancy diabetes, hypertension, HF, or coronary artery disease. GDM, GHTD, peripartum cardiomyopathy (at index pregnancy) were identified using diagnosis coding. Incident HF was assessed from index pregnancy until March 31, 2020. We estimated associations of GDM and/or GHTD with peripartum cardiomyopathy and incident HF. RESULTS: Among 885,873 women (mean age: 30 years, 54,015 with isolated GDM, 43,750 with isolated GHTD, 4,960 with GDM and GHTD), there were 489 HF events over 8 years. Compared to no-GDM and no-GHTD, isolated GDM (adjusted hazard ratio [aHR]: 1.44; 95% CI: 1.02-2.04) and isolated GHTD (aHR: 1.65; 95% CI: 1.17-2.31) were associated with a higher risk of incident HF. The co-occurrence of GDM and GHTD was associated with a higher HF risk (aHR: 2.64; 95% CI: 1.24-5.61). GDM and GHTD increased the risk of peripartum cardiomyopathy (adjusted risk ratio [aRR]: 7.30; 95% CI: 6.92-7.58), similarly to isolated GHTD (aRR: 7.40; 95% CI: 7.23-7.58). CONCLUSIONS: The co-occurrence of GDM and GHTD was associated with a significantly high risk of incident HF.

Dealing With Nonproportional Hazards in Coronary Revascularisation Studies.

The Cox proportional hazards model is one of the most popular statistical tools to model time to event outcomes without the need for specifying the hazards or survival time distributions. The Cox model requires that the ratio of the hazards of the occurrence of the outcome for any 2 individuals remains constant during the entire follow-up. Studies comparing coronary revascularisation strategies, however, might be prone to violations of proportionality by the crossing of the hazard functions over time. Early increases in the risk of cardiovascular outcomes are commonly observed when comparing coronary artery bypass grafting vs percutaneous coronary intervention, whereas decreased risk might be observed later during the follow-up. The same is valid for comparisons between invasive vs conservative coronary revascularisation strategies. In these situations, the statistical power of the Cox model is reduced, and hazard ratios might not be an informative summary measure of treatment effect. In this article, we discuss methods to identify and account for nonproportionality. We illustrate the use of these methods in a case study based on reconstructed data from a coronary revascularisation clinical trial. And finally, we review the cardiovascular literature to estimate how the proportionality assumption has been reported in coronary revascularisation studies recently.

Prediction of birthweight and risk of macrosomia in pregnancies complicated by diabetes.

BACKGROUND: Antenatal detection of accelerated fetal growth and macrosomia in pregnancies complicated by diabetes mellitus is important for patient counseling and management. Sonographic fetal weight estimation is the most commonly used tool to predict birthweight and macrosomia. However, the predictive accuracy of sonographic fetal weight estimation for these outcomes is limited. In addition, an up-to-date sonographic fetal weight estimation is often unavailable before birth. This may result in a failure to identify macrosomia, especially in pregnancies complicated by diabetes mellitus where care providers might underestimate fetal growth rate. Therefore, there is a need for better tools to detect and alert care providers to the potential risk of accelerated fetal growth and macrosomia. OBJECTIVE: This study aimed to develop and validate prediction models for birthweight and macrosomia in pregnancies complicated by diabetes mellitus. STUDY DESIGN: This was a completed retrospective cohort study of all patients with a singleton live birth at ≥36 weeks of gestation complicated by preexisting or gestational diabetes mellitus observed at a single tertiary center between January 2011 and May 2022. Candidate predictors included maternal age, parity, type of diabetes mellitus, information from the most recent sonographic fetal weight estimation (including estimated fetal weight, abdominal circumference z score, head circumference-to-abdomen circumference z score ratio, and amniotic fluid), fetal sex, and the interval between ultrasound examination and birth. The study outcomes were macrosomia (defined as birthweights >4000 and >4500 g), large for gestational age (defined as a birthweight >90th percentile for gestational age), and birthweight (in grams). Multivariable logistic regression models were used to estimate the probability of dichotomous outcomes, and multivariable linear regression models were used to estimate birthweight. Model discrimination and predictive accuracy were calculated. Internal validation was performed using the bootstrap resampling technique. RESULTS: A total of 2465 patients met the study criteria. Most patients had gestational diabetes mellitus (90%), 6% of patients had type 2 diabetes mellitus, and 4% of patients had type 1 diabetes mellitus. The overall proportions of infants with birthweights >4000 g, >4500 g, and >90th percentile for gestational age were 8%, 1%, and 12%, respectively. The most contributory predictor variables were estimated fetal weight, abdominal circumference z score, ultrasound examination to birth interval, and type of diabetes mellitus. The models for the 3 dichotomous outcomes had high discriminative accuracy (area under the curve receiver operating characteristic curve, 0.929-0.979), which was higher than that achieved with estimated fetal weight alone (area under the curve receiver operating characteristic curve, 0.880-0.931). The predictive accuracy of the models had high sensitivity (87%-100%), specificity (84%-92%), and negative predictive values (84%-92%). The predictive accuracy of the model for birthweight had low systematic and random errors (0.6% and 7.5%, respectively), which were considerably smaller than the corresponding errors achieved with estimated fetal weight alone (-5.9% and 10.8%, respectively). The proportions of estimates within 5%, 10%, and 15% of the actual birthweight were high (52.3%, 82.9%, and 94.9%, respectively). CONCLUSION: The prediction models developed in the current study were associated with greater predictive accuracy for macrosomia, large for gestational age, and birthweight than the current standard of care that includes estimated fetal weight alone. These models may assist care providers in counseling patients regarding the optimal timing and mode of delivery.

The Glucose Challenge Test in Pregnancy Identifies Future Risk of Diabetes.

CONTEXT: Women with gestational diabetes (GDM) have an increased future risk of type 2 diabetes but, in practice, their recommended postpartum glucose tolerance testing is often missed or substituted with measurement of A1c instead. OBJECTIVE: We hypothesized that the antenatal screening glucose challenge test (GCT) should predict future diabetes risk and, if so, would have thresholds that identify the same degree of risk as the diagnosis of prediabetes on postpartum measurement of A1c. METHODS: With population-based administrative databases, we identified all women in Ontario, Canada, who had a GCT in pregnancy with delivery between January 2007 and December 2017, followed by measurement of A1c and fasting glucose within 2 years postpartum (n = 141 858, including 19 034 with GDM). Women were followed over a median of 3.5 years for the development of diabetes. RESULTS: Under the assumption of a linear exposure effect, the 1-hour post-challenge glucose concentration on the GCT was associated with an increased likelihood of developing diabetes (hazard ratio 1.39; 95% CI, 1.38-1.40). A GCT threshold of 8.0 mmol/L predicted the same 5-year risk of diabetes (6.0%; 95% CI, 5.8-6.2) as postpartum A1c 5.7% (identifying prediabetes). Moreover, in women with GDM, a GCT threshold of 9.8 mmol/L equaled prediabetes on postpartum A1c in predicting a 5-year risk of diabetes of 16.5% (14.8-18.2). CONCLUSION: The GCT offers predictive capacity for future diabetes in pregnant women. In women with GDM, this insight could identify those at highest risk of diabetes, toward whom postpartum screening efforts should be most strongly directed.

Association of Beta-Blocker Therapy With Cardiovascular Outcomes in Patients With Stable Ischemic Heart Disease.

BACKGROUND: Previous studies have failed to show a cardioprotective benefit of beta-blockers in patients with stable coronary artery disease (CAD). OBJECTIVES: This study sought to determine the association between beta-blockers and cardiovascular events in patients with stable CAD using a new user design. METHODS: All patients aged >66 years undergoing elective coronary angiography in Ontario, Canada, from 2009 to 2019 with diagnosed obstructive CAD were included. Exclusion criteria included heart failure or a recent myocardial infarction, as well as having a beta-blocker prescription claim in the previous year. Beta-blocker use was defined as having at least 1 beta-blocker prescription claim in the 90 days preceding or after the index coronary angiography. The main outcome was a composite of all-cause mortality and hospitalization for heart failure or myocardial infarction. Inverse probability of treatment weighting using the propensity score was used to account for confounding. RESULTS: This study included 28,039 patients (mean age: 73.0 ± 5.6 years; 66.2% male), and 12,695 of those (45.3%) were newly prescribed beta-blockers. The 5-year risks of the primary outcome were 14.3% in the beta-blocker group and 16.1% in the no beta-blocker group (absolute risk reduction: -1.8%; 95% CI: -2.8 to -0.8; HR: 0.92; 95% CI: 0.86-0.98; P = 0.006). This result was driven by reductions in myocardial infarction hospitalization (cause-specific HR: 0.87; 95% CI: 0.77-0.99; P = 0.031), whereas no differences were observed in all-cause death or heart failure hospitalization. CONCLUSIONS: In patients with angiographically documented stable CAD without heart failure or a recent myocardial infarction, beta-blockers were associated with a small but significant reduction in cardiovascular events at 5 years.