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.

Association of Different Prescribing Patterns for Oral Corticosteroids With Fracture Preventive Care Among Older Adults in the UK and Ontario.

Importance: Identifying and mitigating modifiable gaps in fracture preventive care for people with relapsing-remitting conditions such as eczema, asthma, and chronic obstructive pulmonary disease who are prescribed high cumulative oral corticosteroid doses may decrease fracture-associated morbidity and mortality. Objective: To estimate the association between different oral corticosteroid prescribing patterns and appropriate fracture preventive care, including treatment with fracture preventive care medications, among older adults with high cumulative oral corticosteroid exposure. Design, Setting, and Participants: This cohort study included 65 195 participants with UK electronic medical record data from the Clinical Practice Research Datalink (January 2, 1998, to January 31, 2020) and 28 674 participants with Ontario, Canada, health administrative data from ICES (April 1, 2002, to September 30, 2020). Participants were adults 66 years or older with eczema, asthma, or chronic obstructive pulmonary disease receiving prescriptions for oral corticosteroids with cumulative prednisolone equivalent doses of 450 mg or higher within 6 months. Data were analyzed October 22, 2020, to September 6, 2022. Exposures: Participants with prescriptions crossing the 450-mg cumulative oral corticosteroid threshold in less than 90 days were classified as having high-intensity prescriptions, and participants crossing the threshold in 90 days or more as having low-intensity prescriptions. Multiple alternative exposure definitions were used in sensitivity analyses. Main Outcomes and Measures: The primary outcome was prescribed fracture preventive care. A secondary outcome was major osteoporotic fracture. Individuals were followed up from the date they crossed the cumulative oral corticosteroid threshold until their outcome or the end of follow-up (up to 1 year after index date). Rates were calculated for fracture preventive care and fractures, and hazard ratios (HRs) were estimated from Cox proportional hazards regression models comparing high- vs low-intensity oral corticosteroid prescriptions. Results: In both the UK cohort of 65 195 participants (mean [IQR] age, 75 [71-81] years; 32 981 [50.6%] male) and the Ontario cohort of 28 674 participants (mean [IQR] age, 73 [69-79] years; 17 071 [59.5%] male), individuals with high-intensity oral corticosteroid prescriptions had substantially higher rates of fracture preventive care than individuals with low-intensity prescriptions (UK: 134 vs 57 per 1000 person-years; crude HR, 2.34; 95% CI, 2.19-2.51, and Ontario: 73 vs 48 per 1000 person-years; crude HR, 1.49; 95% CI, 1.29-1.72). People with high- and low-intensity oral corticosteroid prescriptions had similar rates of major osteoporotic fractures (UK: crude rates, 14 vs 13 per 1000 person-years; crude HR, 1.07; 95% CI, 0.98-1.15 and Ontario: crude rates, 20 vs 23 per 1000 person-years; crude HR, 0.87; 95% CI, 0.79-0.96). Results from sensitivity analyses suggested that reaching a high cumulative oral corticosteroid dose within a shorter time, with fewer prescriptions, or with fewer or shorter gaps between prescriptions, increased fracture preventive care prescribing. Conclusions: The results of this cohort study suggest that older adults prescribed high cumulative oral corticosteroids across multiple prescriptions, or with many or long gaps between prescriptions, may be missing opportunities for fracture preventive care.

The Association of Sodium-Glucose Cotransporter 2 Inhibitors With Cardiovascular Outcomes in Anthracycline-Treated Patients With Cancer.

Background: Sodium glucose cotransporter-2 inhibitors (SGLT2is) are hypothesized to reduce the risk of anthracycline-associated cardiotoxicity. Objectives: This study sought to determine the association between SGLT2is and cardiovascular disease (CVD) after anthracycline-containing chemotherapy. Methods: Using administrative data sets, we conducted a population-based cohort study of people >65 years of age with treated diabetes and no prior heart failure (HF) who received anthracyclines between January 1, 2016, and December 31, 2019. After estimating propensity scores for SGLT2i use, the average treatment effects for the treated weights were used to reduce baseline differences between SGLT2i-exposed and -unexposed controls. The outcomes were hospitalization for HF, incident HF diagnoses (in- or out-of-hospital), and documentation of any CVD in future hospitalizations. Death was treated as a competing risk. Cause-specific HRs for each outcome were determined for SGLT2i-treated people relative to unexposed controls. Results: We studied 933 patients (median age 71.0 years, 62.2% female), 99 of whom were SGLT2i treated. During a median follow-up of 1.6 years, there were 31 hospitalizations for HF (0 in the SGLT2i group), 93 new HF diagnoses, and 74 hospitalizations with documented CVD. Relative to controls, SGLT2i exposure was associated with HR of 0 for HF hospitalization (P < 0.001) but no significant difference in incident HF diagnosis (HR: 0.55; 95% CI: 0.23-1.31; P = 0.18) or CVD diagnosis (HR: 0.39; 95% CI: 0.12-1.28; P = 0.12). There was no significant difference in mortality (HR: 0.63; 95% CI: 0.36-1.11; P = 0.11). Conclusions: SGLT2is may reduce the rate of HF hospitalization after anthracycline-containing chemotherapy. This hypothesis warrants further testing in randomized controlled trials.

Insulin Use in Type 2 Diabetes and the Risk of Dementia: A Comparative Population-Based Cohort Study.

OBJECTIVE: Evidence of an increased dementia risk with insulin use in type 2 diabetes is weakened by confounding by indication and disease severity. Herein we reassess this association, while accounting for confounding through design and analysis. RESEARCH DESIGN AND METHODS: Using administrative health care data from British Columbia, Canada, we identified patients diagnosed with type 2 diabetes in 1998-2016. To adjust for confounding by diabetes severity through design, we compared new users of insulin to new users of a noninsulin class, both from a restricted cohort of those who previously received two noninsulin antihyperglycemic classes. We further adjusted for confounding using 1) conventional multivariable adjustment and 2) inverse probability of treatment weighting (IPTW) based on the high-dimensional propensity score algorithm. The hazard ratio [HR] (95% CI) of dementia was estimated using cause-specific hazards models with death as a competing risk. RESULTS: The analytical comparative cohort included 7,863 insulin versus 25,230 noninsulin users. At baseline, insulin users were more likely to have worse health indicators. A total of 78 dementia events occurred over a median (interquartile range) follow-up of 3.9 (5.9) years among insulin users, and 179 events occurred over 4.6 (4.4) years among noninsulin users. The HR (95% CI) of dementia for insulin use versus noninsulin use was 1.68 (1.29-2.20) before adjustment and 1.39 (1.05-1.86) after multivariable adjustment, which was further attenuated to 1.14 (0.81-1.60) after IPTW. CONCLUSIONS: Among individuals with type 2 diabetes previously exposed to two noninsulin antihyperglycemic medications, no significant association was observed between insulin use and all-cause dementia.

Lipoprotein(a) Does Not Predict Thrombotic Events and In-Hospital Outcomes in Patients with COVID-19.

The prothrombotic and proinflammatory properties of lipoprotein(a) (Lp(a)) have been hypothesized to play a role in the pathogenesis of severe COVID-19; however, the prognostic impact of Lp(a) on the clinical course of COVID-19 remains controversial. This study aimed to investigate whether Lp(a) may be associated with biomarkers of thrombo-inflammation and the occurrence of thrombotic events or adverse clinical outcomes in patients hospitalized for COVID-19. We consecutively enrolled a cohort of patients hospitalized for COVID-19 and collected blood samples for Lp(a) assessment at hospital admission. A prothrombotic state was evaluated through D-dimer levels, whereas a proinflammatory state was evaluated through C-reactive protein (CRP), procalcitonin, and white blood cell (WBC) levels. Thrombotic events were marked by the diagnosis of deep or superficial vein thrombosis (DVT or SVT), pulmonary embolism (PE), stroke, transient ischemic attack (TIA), acute coronary syndrome (ACS), and critical limb ischemia (CLI). The composite clinical end point of intensive care unit (ICU) admission/in-hospital death was used to evaluate adverse clinical outcomes. Among 564 patients (290 (51%) men, mean age of 74 ± 17 years) the median Lp(a) value at hospital admission was 13 (10-27) mg/dL. During hospitalization, 64 (11%) patients were diagnosed with at least one thrombotic event and 83 (15%) patients met the composite clinical end point. Lp(a), as either a continuous or categorical variable, was not associated with D-dimer, CRP, procalcitonin, and WBC levels (p > 0.05 for all correlation analyses). In addition, Lp(a) was not associated with a risk of thrombotic events (p > 0.05 for multi-adjusted odds ratios) nor with a risk of adverse clinical outcomes (p > 0.05 for multi-adjusted hazard ratios). In conclusion, Lp(a) does not influence biomarkers of plasma thrombotic activity and systemic inflammation nor has any impact on thrombotic events and adverse clinical outcomes in patients hospitalized for COVID-19.

Patterns of diabetes testing for older adults without diabetes in Ontario's nursing homes: A population-based study.

BACKGROUND: Asymptomatic diabetes testing may be of limited value for older nursing home residents, but most diabetes guidelines lack upper-age cutoffs for screening cessation. We evaluated patterns of glycated hemoglobin (HbA1c) and serum blood glucose (SBG) testing among older residents without diabetes in Ontario, Canada. METHODS: This population-based retrospective cohort study used provincial health administrative data from ICES to identify older nursing home residents in Ontario without diabetes between January 1, 2015 and December 31, 2018. We examined HbA1c and glucose testing rates overall, by age, sex, and near end-of-life. The number of tests needed to identify one case of diabetes (using HbA1c thresholds of 6.5% and 8.0%) were also calculated. RESULTS: Among 102,923 older nursing home residents (70.3% women; average age 85.6 ± SD 7.7 years), 46.1% of residents received ≥1 HbA1c test over an average follow-up period of 2.15 (± SD 1.49) years, and 18.2% of these tested residents received ≥4 HbA1c tests. The crude HbA1c testing rate was 52.6 tests/100 person-years (95% CI 52.3-52.9). Testing rates among residents aged ≥80 years was 50.7 HbA1c tests/100 person-years (95% CI 50.4-51.0), and 47.8 tests/100 person-years (95% CI 46.5-49.0) among residents near end-of-life. The number of tests to identify a case of diabetes (HbA1c ≥ 6.5%) was 44, while the number of tests to identify a case of actionable diabetes (HbA1c ≥ 8%) was 310. Less than 1% of residents with an HbA1c test met criteria for actionable diabetes. CONCLUSIONS: Nursing home residents without diabetes receive frequent diabetes testing, with high testing rates even in residents over 80 years old and residents near end-of-life. The high number of tests needed to identify a case of actionable diabetes highlights the urgent need to re-evaluate diabetes testing practices in nursing homes.

Associations of Mid- and Late-Life Severe Hypoglycemic Episodes With Incident Dementia Among Patients With Type 2 Diabetes: A Population-Based Cohort Study.

OBJECTIVE: Severe hypoglycemia is associated with an increased risk of dementia. We examined if the association is consistently present in mid- and late-life hypoglycemia. RESEARCH DESIGN AND METHODS: Using health care data from Population Data BC, we created a base cohort of patients age ≥40 years with incident type 2 diabetes. Exposure was the first occurrence of severe hypoglycemia (hospitalization or physician visit). We assessed exposure versus no exposure in mid- (age 45-64 years) and late-life (age 65-84 years) cohorts. Index date was the later of the 45th birthday (midlife cohort), 65th birthday (late-life cohort), or diabetes diagnosis. Those with hypoglycemia or dementia before the index date were excluded. Patients were followed from index date until dementia diagnosis, death, emigration, or 31 December 2018. Exposure was modeled as time dependent. We adjusted for confounding using propensity score weighting. Dementia risk was estimated using cause-specific hazards models with death as a competing risk. RESULTS: Of 221,683 patients in the midlife cohort, 1,793 experienced their first severe hypoglycemic event. Over a median of 9.14 years, 3,117 dementia outcomes occurred (32 among exposed). Of 223,940 patients in the late-life cohort, 2,466 experienced their first severe hypoglycemic event. Over a median of 6.7 years, 15,997 dementia outcomes occurred (158 among exposed). The rate of dementia was higher for those with (vs. without) hypoglycemia in both the mid- (hazard ratio 2.85; 95% CI 1.72-4.72) and late-life (2.38; 1.83-3.11) cohorts. CONCLUSIONS: Both mid- and late-life hypoglycemia were associated with approximately double the risk of dementia, indicating the need for prevention throughout the life course of those with diabetes.

Hypoglycaemia and the risk of dementia: a population-based cohort study using exposure density sampling.

BACKGROUND: Previous studies have shown hypoglycaemia to be associated with an increased risk of dementia; however, there are several design challenges to consider. The objective of this study is to assess the association between hypoglycaemia and dementia while addressing these challenges using a lag period, exposure density sampling (EDS) and inverse probability of treatment weighting (IPTW). METHODS: This was a population-based cohort using data (1996-2018) from British Columbia, Canada. From a cohort of incident type 2 diabetes patients aged 40-70 years, we created a dynamic sub-cohort of hypoglycaemia-exposed (≥1 episode requiring hospitalization or a physician visit) and unexposed individuals using EDS, in which four unexposed individuals per one exposed were randomly selected into risk sets based on diabetes duration and age. Follow-up was until dementia diagnosis, death, emigration or 31 December 2018. Those diagnosed with dementia within 2 years of follow-up were censored. We adjusted for confounding using IPTW and estimated the hazard ratio (HR, 95% CI) of dementia using weighted conditional cause-specific hazards risk models with death as a competing risk. RESULTS: Among 13 970 patients with incident type 2 diabetes, 2794 experienced hypoglycaemia. There were 329 dementia events over a median (interquartile range: IQR) follow-up of 5.03 (5.7) years. IPTW resulted in well-balanced groups with weighted incidence rates (95% CI) of 4.59 (3.52, 5.98)/1000 person-years among exposed and 3.33 (2.58, 3.88)/1000 person-years among unexposed participants. The risk of dementia was higher among those with hypoglycaemia (HR, 1.83; 95% CI 1.31, 2.57). CONCLUSIONS: After addressing several methodological challenges, we showed that hypoglycaemia contributes to an increased risk of all-cause dementia among patients with type 2 diabetes.

Benefits and Harms of Deprescribing Antihyperglycemics for Adults With Type 2 Diabetes: A Systematic Review.

OBJECTIVES: Contemporary guidelines suggest relaxed glycemic targets in populations with type 2 diabetes mellitus (T2DM) at risk of hypoglycemia, including people with multimorbidity, limited life expectancy or frailty. However, overtreatment remains commonplace. To inform safe deprescribing, a previous systematic review investigated the benefits and harms of deprescribing antihyperglycemics, but identified only limited, very low-quality evidence. We sought to update that review and identify and describe newly published literature on the effects of deprescribing antihyperglycemics in older adults with T2DM. METHODS: We searched MEDLINE, EMBASE and the Cochrane Library (July 2015 to January 2021) for controlled studies published in English addressing the effects of deprescribing vs continuing antihyperglycemics in adults with T2DM. Two independent reviewers performed title, abstract and full-text screening, data extraction and risk-of-bias assessment. Cochrane's risk-of-bias tools, RoB 2 and ROBINS-I, were used. The findings were summarized narratively. GRADE (Grading of Recommendations, Assessment, Development and Evaluations) was used to evaluate the evidence. RESULTS: We identified 4 additional investigations-2 randomized controlled trials and 2 retrospective cohort studies. After deprescribing, 3 studies reported no clinically significant changes in glucose management and 2 studies reported reductions in adverse events (e.g. hypoglycemia, all-cause mortality and nonspine fractures). However, based on GRADE assessment, we found very low certainty of the evidence due to concerns of risk of bias (e.g. unmeasured confounding), imprecision, and indirectness. CONCLUSIONS: Deprescribing antihyperglycemic medications in older adults with T2DM is likely feasible and safe, and benefits may outweigh the harms. However, the evidence indicates very low certainty. Additional deprescribing studies are needed with rigorous methodologies and reporting.

Comparing estrogen-based hormonal contraceptives and hormone therapy on bone mineral density in women with premature ovarian insufficiency: a systematic review.

IMPORTANCE: Premature ovarian insufficiency (POI) is a condition associated with estrogen deficiency which leads to decreased bone mineral density and an increased risk of osteoporosis and fractures. Estrogen-based hormone therapy is an integral component of treatment; however, to date the ideal hormone formulation for optimizing bone health has not been established. OBJECTIVE: To assess the effects of estrogen-based oral contraceptives (OCP) versus hormone therapy (HT) on bone mineral density (BMD) in women with POI. EVIDENCE REVIEW: A systematic review of Ovid MEDLINE, EMBASE, Cochrane Library, and Web of Science databases was conducted from conception until December 2020. Randomized controlled trials (RCTs) and observational studies that met inclusion criteria were included in the analysis. Risk of bias was assessed with the Newcastle-Ottawa Quality Assessment Scale for cohort studies and the Cochrane Risk of Bias for RCTs. The study protocol was registered with the International Prospective Register of Systematic Reviews and adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. FINDINGS: Our search yielded 1,227 studies; 3 RCTs and 2 observational cohort studies met inclusion criteria and were included in our study. The largest subpopulation was Turner Syndrome (n = 625), followed by idiopathic POI (n = 146). Of the four studies that assessed changes in BMD, two studies reported a significant increase in lumbar spine BMD with HT compared with OCP (+0.050 g/cm2, P < 0.025; +0.019 g/cm2, P < 0.01), one study found similar improvement in lumbar spine BMD across treatments (HT -0.003 g/cm2, P = 0.824), and one study did not directly compare treatments. Effects on bone turnover markers were inconsistent across three studies that evaluated this outcome. CONCLUSIONS AND RELEVANCE: This is the first systematic review to include studies that directly compared OCP and HT on bone outcomes in POI. While two studies reported increased lumbar spine BMD with HT, this result was not consistently found across studies. There were important differences in POI etiology, treatment regimens and formulations, and risk of bias was high in many of the studies. These results indicate future, larger-scale trials are needed to further understand the optimal hormone therapy for bone density in POI.

Association of Diabetes Duration and Glycemic Control With Stroke Rate in Patients With Atrial Fibrillation and Diabetes: A Population-Based Cohort Study.

Background There are limited data on the association of diabetes duration and glycemic control with stroke risk in atrial fibrillation (AF). Our objective was to study the association of diabetes duration and glycated hemoglobin (HbA1c) with the rate of stroke in people with diabetes and newly diagnosed AF. Methods and Results This was a population-based cohort study using linked administrative data sets. We studied 37 209 individuals aged ≥66 years diagnosed with AF in Ontario between April 2009 and March 2019, who had diabetes diagnosed 1 to 16 years beforehand. The primary outcome was hospitalization for stroke at 1 year. Cause-specific hazard regression was used to model the association of diabetes duration and glycated hemoglobin (HbA1c) with the rate of stroke. Restricted cubic spline analyses showed increasing hazard ratios (HR) for stroke with longer diabetes duration that plateaued after 10 years and increasing HRs for stroke with HbA1c levels >7%. Relative to patients with <5 years diabetes duration, stroke rates were significantly higher for patients with ≥10 years duration (HR, 1.45; 95% CI, 1.16-1.82; P=0.001), while diabetes duration 5 to <10 years was not significantly different. Relative to glycated hemoglobin 6% to <7%, values ≥8% were associated with higher stroke rates (HR, 1.44; 95% CI, 1.12-1.84; P=0.004), while other HbA1c categories were not significantly different. Conclusions Longer diabetes duration and higher glycated hemoglobin were associated with significantly higher stroke rates in patients with AF and diabetes. Models for stroke risk prediction and preventive care in AF may be improved by considering patients' diabetes characteristics.