Treatment patterns of patients with HR+/HER2- metastatic breast cancer receiving CDK4/6 inhibitor-based regimens: a cohort study in the French nationwide healthcare database.

PURPOSE: To assess real-world treatment patterns in patients diagnosed with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (mBC) who received cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with an aromatase inhibitor (AI) or fulvestrant at first line. METHODS: Patient characteristics, treatment history, and outcomes data were extracted from the French 'Système National des Données de Santé' (SNDS) database for patients diagnosed with HR+/HER2- mBC between January 2014 and June 2019 and who received combination therapy with a CDK4/6 inhibitor and endocrine therapy. Kaplan-Meier methodology was used to assess time to next treatment (TTNT) and time to treatment discontinuation (TTTD). RESULTS: The cohort comprised 6061 patients including 4032 patients who received CDK4/6 inhibitors + AIs and 2029 patients who received CDK4/6 inhibitors + fulvestrant. Median follow-up was 13.5 months (IQR 9.5-18.1). The median TTTD of first line treatment with CDK4/6 inhibitors + AIs and CDK4/6 inhibitors + fulvestrant was 17.3 months (95% CI 16.8-17.9) and 9.7 months (95% CI 9.0-10.2), respectively. Chemotherapy was the most common second line therapy. Median TTTD of subsequent treatment lines was progressively shorter following first line treatment with CDK4/6 inhibitors + AIs (2nd line: 4.6 months (95% CI 4.4-4.9) and with CDK4/6 inhibitors + fulvestrant (2nd line: 4.7 months (95% CI 4.3-5.1). TTNT was longer than TTTD across lines of therapy. CONCLUSION: This real-world analysis confirms the effectiveness of CDK4/6 inhibitor-based regimens in French patients and highlights the frequent use of chemotherapy as second line therapy.

Remdesivir Reduced Mortality in Immunocompromised Patients Hospitalized for COVID-19 Across Variant Waves: Findings From Routine Clinical Practice.

BACKGROUND: Immunocompromised patients are at high risk of severe coronavirus disease 2019 (COVID-19) and death, yet treatment strategies for immunocompromised patients hospitalized for COVID-19 reflect variations in clinical practice. In this comparative effectiveness study, we investigated the effect of remdesivir treatment on inpatient mortality among immunocompromised patients hospitalized for COVID-19 across all variants of concern (VOC) periods. METHODS: Data for immunocompromised patients hospitalized for COVID-19 between December 2020 and April 2022 were extracted from the US PINC AITM Healthcare Database. Patients who received remdesivir within 2 days of hospitalization were matched 1:1 using propensity score matching to patients who did not receive remdesivir. Additional matching criteria included admission month, age group, and hospital. Cox proportional hazards models were used to examine the effect of remdesivir on risk of 14- and 28-day mortality during VOC periods. RESULTS: A total of 19 184 remdesivir patients were matched to 11 213 non-remdesivir patients. Overall, 11.1% and 17.7% of remdesivir patients died within 14 and 28 days, respectively, compared with 15.4% and 22.4% of non-remdesivir patients. Remdesivir was associated with a reduction in mortality at 14 (hazard ratio [HR], 0.70; 95% confidence interval, .62-.78) and 28 days (HR, 0.75; 95% CI, .68-.83). The survival benefit remained significant during the pre-Delta, Delta, and Omicron periods. CONCLUSIONS: Prompt initiation of remdesivir in immunocompromised patients hospitalized for COVID-19 is associated with significant survival benefit across all variant waves. These findings provide much-needed evidence relating to the effectiveness of a foundational treatment for hospitalized COVID-19 patients among a high-risk population.

The association between offspring birthweight and future risk of maternal diabetes: A population-based study.

AIMS: As an indicator of maternal cardiometabolic health, newborn birthweight may be an important predictor of maternal type 2 diabetes mellitus (diabetes). We evaluated the relation between offspring birthweight and onset of maternal diabetes after pregnancy. METHODS: This retrospective cohort study used linked population-based health databases from Ontario, Canada. We included women aged 16-50 years without pre-pregnancy diabetes, and who had a live birth between 2006 and 2014. We used Cox proportional hazard regression to evaluate the association between age- and sex-standardized offspring birthweight percentile categories and incident maternal diabetes, while adjusting for maternal age, parity, year, ethnicity, gestational diabetes (GDM) and hypertensive disorders of pregnancy (HDP). Results were further stratified by the presence of GDM in the index pregnancy. RESULTS: Of 893,777 eligible participants, 14,329 (1.6%) women were diagnosed with diabetes over a median (IQR) of 4.4 (1.5-7.4) years of follow-up. There was a continuous positive relation between newborn birthweight above the 75th percentile and maternal diabetes. Relative to a birthweight between the 50th and 74.9th percentiles, women whose newborn had a birthweight between the 97th and 100th percentiles had an adjusted hazards ratio (aHR) of diabetes of 2.30 (95% CI 2.16-2.46), including an aHR of 2.01 (95% CI 1.83-2.21) among those with GDM, and 2.59 (2.36-2.84) in those without GDM. CONCLUSIONS: A higher offspring birthweight signals an increased risk of maternal diabetes, offering another potentially useful way to identify women especially predisposed to diabetes.

The association between immigration status and the development of type 2 diabetes in women with a prior diagnosis of gestational diabetes: A population-based study.

AIMS: The aim of this study was to examine the influence of immigration status and region of origin on the risk of type 2 diabetes in women with prior gestational diabetes (GDM). METHODS: This retrospective population-based cohort study included women with gestational diabetes (GDM) aged 16 to 50 years in Ontario, Canada, who gave birth between 2006 and 2014. We compared the incidence of type 2 diabetes after delivery between long-term residents and immigrants-overall, by time since immigration and by region of-using Cox regression adjusted for age, year, neighbourhood income, rurality, infant birth weight and presence of hypertensive disorders of pregnancy (HDP). RESULTS: Among 38,515 women with prior GDM (42% immigrants), immigrants had a significantly higher risk of type 2 diabetes compared with long-term residents (adjusted hazard ratio [HR] 1.19, 95% confidence interval [CI] 1.13-1.26), with no meaningful difference based on time since immigration. The highest adjusted relative risks of type 2 diabetes compared with long-term residents were found for immigrants from Sub-Saharan Africa (HR 1.63, 95% CI 1.40-1.90), Latin America/Caribbean (HR 1.44, 95% CI 1.28-1.62) and South Asia (HR 1.34, 95% CI 1.25-1.44). CONCLUSIONS: Immigration is associated with a significantly higher risk of type 2 diabetes after GDM, particularly for women from certain low- and middle-income countries. Diabetes prevention strategies will need to consider the unique needs of immigrants from these regions.

External control arms for rare diseases: building a body of supporting evidence.

Comparator arms in randomized clinical trials may be impractical and/or unethical to assemble in rare diseases. In the absence of comparator arms, evidence generated from external control studies has been used to support successful regulatory submissions and health technology assessments (HTA). However, conducting robust and rigorous external control arm studies is challenging and despite all efforts, residual biases may remain. As a result, regulatory and HTA agencies may request additional external control analyses so that decisions may be made based upon a body of supporting evidence.This paper introduces external control studies and provides an overview of the key methodological issues to be considered in the design of these studies. A series of case studies are presented in which evidence derived from one or more external controls was submitted to regulatory and HTA agencies to provide support for the consistency of findings.

Mortality trends in type 1 diabetes: a multicountry analysis of six population-based cohorts.

AIMS/HYPOTHESIS: Mortality has declined in people with type 1 diabetes in recent decades. We examined how the pattern of decline differs by country, age and sex, and how mortality trends in type 1 diabetes relate to trends in general population mortality. METHODS: We assembled aggregate data on all-cause mortality during the period 2000-2016 in people with type 1 diabetes aged 0-79 years from Australia, Denmark, Latvia, Scotland, Spain (Catalonia) and the USA (Kaiser Permanente Northwest). Data were obtained from administrative sources, health insurance records and registries. All-cause mortality rates in people with type 1 diabetes, and standardised mortality ratios (SMRs) comparing type 1 diabetes with the non-diabetic population, were modelled using Poisson regression, with age and calendar time as quantitative variables, describing the effects using restricted cubic splines with six knots for age and calendar time. Mortality rates were standardised to the age distribution of the aggregate population with type 1 diabetes. RESULTS: All six data sources showed a decline in age- and sex-standardised all-cause mortality rates in people with type 1 diabetes from 2000 to 2016 (or a subset thereof), with annual changes in mortality rates ranging from -2.1% (95% CI -2.8%, -1.3%) to -5.8% (95% CI -6.5%, -5.1%). All-cause mortality was higher for male individuals and for older individuals, but the rate of decline in mortality was generally unaffected by sex or age. SMR was higher in female individuals than male individuals, and appeared to peak at ages 40-70 years. SMR declined over time in Denmark, Scotland and Spain, while remaining stable in the other three data sources. CONCLUSIONS/INTERPRETATION: All-cause mortality in people with type 1 diabetes has declined in recent years in most included populations, but improvements in mortality relative to the non-diabetic population are less consistent.

BMI and risk of gestational diabetes among women of South Asian and Chinese ethnicity: a population-based study.

AIMS/HYPOTHESIS: The aim of this study was to examine how BMI influences the association between Asian ethnicity and risk of gestational diabetes (GDM). METHODS: This population-based cohort study included pregnant women without pre-existing diabetes mellitus in Ontario, Canada between 2012 and 2014. Women of Chinese and South Asian ethnicity were identified using a validated surname algorithm. GDM was ascertained using hospitalisation codes. The relationship between ethnicity and GDM was modelled using modified Poisson regression, adjusted for maternal age, pre-pregnancy BMI, parity, previous GDM, long-term residency status, income quintile and smoking status. An interaction term between ethnicity and pre-pregnancy BMI was tested. RESULTS: Of 231,618 pregnant women, 9289 (4.0%) were of South Asian ethnicity and 12,240 (5.3%) were of Chinese ethnicity. Relative to women from the general population, in whom prevalence of GDM was 4.3%, the adjusted RR of GDM was higher among those of South Asian ethnicity (1.81 [95% CI 1.64, 1.99]) and Chinese ethnicity (1.66 [95% CI 1.53, 1.80]). The association between GDM and Asian ethnicity remained significant across BMI categories but differed according to BMI. The prevalence of GDM exceeded 5% at an estimated BMI of 21.5 kg/m2 among South Asian women, 23.0 kg/m2 among Chinese women and 29.5 kg/m2 among the general population. CONCLUSIONS/INTERPRETATION: The risk of GDM is significantly higher in South Asian and Chinese women, whose BMI is lower than that of women in the general population. Accordingly, targeted GDM prevention strategies may need to consider lower BMI cut-points for Asian populations.

Development and validation of a cardiovascular risk prediction model in type 1 diabetes.

AIMS/HYPOTHESIS: We aimed to report current rates of CVD in type 1 diabetes and to develop a CVD risk prediction tool for type 1 diabetes. METHODS: A cohort of 27,527 people with type 1 diabetes without prior CVD was derived from the national register in Scotland. Incident CVD events during 199,552 person-years of follow-up were ascertained using hospital admissions and death registers. A Poisson regression model of CVD was developed and then validated in the Swedish National Diabetes Register (n = 33,183). We compared the percentage with a high 10 year CVD risk (i.e., ≥10%) using the model with the percentage eligible for statins using current guidelines by age. RESULTS: The age-standardised rate of CVD per 100,000 person-years was 4070 and 3429 in men and women, respectively, with type 1 diabetes in Scotland, and 4014 and 3956 in men and women in Sweden. The final model was well calibrated (Hosmer-Lemeshow test p > 0.05) and included a further 22 terms over a base model of age, sex and diabetes duration (C statistic 0.82; 95% CI 0.81, 0.83). The model increased the base model C statistic from 0.66 to 0.80, from 0.60 to 0.75 and from 0.62 to 0.68 in those aged <40, 40-59 and ≥ 60 years, respectively (all p values <0.005). The model required minimal calibration in Sweden and had a C statistic of 0.85. Under current guidelines, >90% of those aged 20-39 years and 100% of those ≥40 years with type 1 diabetes were eligible for statins, but it was not until age 65 upwards that 100% had a modelled risk of CVD ≥10% in 10 years. CONCLUSIONS/INTERPRETATION: A prediction tool such as that developed here can provide individualised risk predictions. This 10 year CVD risk prediction tool could facilitate patient discussions regarding appropriate statin prescribing. Apart from 10 year risk, such discussions may also consider longer-term CVD risk, the potential for greater benefits from early vs later statin intervention, the potential impact on quality of life of an early CVD event and evidence on safety, all of which could influence treatment decisions, particularly in younger people with type 1 diabetes.

Risk Factor Control and Cardiovascular Event Risk in People With Type 2 Diabetes in Primary and Secondary Prevention Settings.

BACKGROUND: To examine the association between the degree of risk factor control and cardiovascular disease (CVD) risk in type 2 diabetes and to assess if the presence of cardio-renal disease modifies these relationships. METHODS: A retrospective cohort study using data from English practices from CPRD GOLD (Clinical Practice Research Datalink) and the SCI-Diabetes dataset (Scottish Care Information-Diabetes), with linkage to hospital and mortality data. We identified 101 749 with type 2 diabetes (T2D) in CPRD matched with 378 938 controls without diabetes and 330 892 with type 2 diabetes in SCI-Diabetes between 2006 and 2015. The main exposure was number of optimized risk factors: nonsmoker, total cholesterol ≤4 mmol/L, triglycerides ≤1.7 mmol/L, glycated haemoglobin (HbA1c) ≤53 mmol/mol (≤7.0%), systolic blood pressure <140mm Hg, or <130 mm Hg if high risk. Cox models were used to assess cardiovascular risk associated with levels of risk factor control. RESULTS: In CPRD, the mean baseline age in T2D was 63 years and 28% had cardio-renal disease (SCI-Diabetes: 62 years; 35% cardio-renal disease). Over 3 years follow-up (SCI-Diabetes: 6 years), CVD events occurred among 27 900 (27%) CPRD-T2D, 101 362 (31%) SCI-Diabetes-T2D, and 75 520 (19%) CPRD-controls. In CPRD, compared with controls, T2D participants with optimal risk factor control (all risk factors controlled) had a higher risk of CVD events (adjusted hazard ratio, 1.21; 95% confidence interval, 1.12-1.29). In T2D participants from CPRD and SCI-Diabetes, pooled hazard ratios for CVD associated with 5 risk factors being elevated versus optimal risk factor control were 1.09 (95% confidence interval, 1.01-1.17) in people with cardio-renal disease but 1.96 (95% confidence interval, 1.82-2.12) in people without cardio-renal disease. People without cardio-renal disease were younger and more likely to have likely to have suboptimal risk factor control but had fewer prescriptions for risk factor modifying medications than those with cardio-renal disease. CONCLUSIONS: Optimally managed people with T2D have a 21% higher CVD risk when compared with controls. People with T2D without cardio-renal disease would be predicted to benefit greatly from CVD risk factor intervention.

Prediction of individual life-years gained without cardiovascular events from lipid, blood pressure, glucose, and aspirin treatment based on data of more than 500 000 patients with Type 2 diabetes mellitus.

AIMS: Although group-level effectiveness of lipid, blood pressure, glucose, and aspirin treatment for prevention of cardiovascular disease (CVD) has been proven by trials, important differences in absolute effectiveness exist between individuals. We aim to develop and validate a prediction tool for individualizing lifelong CVD prevention in people with Type 2 diabetes mellitus (T2DM) predicting life-years gained without myocardial infarction or stroke. METHODS AND RESULTS: We developed and validated the Diabetes Lifetime-perspective prediction (DIAL) model, consisting of two complementary competing risk adjusted Cox proportional hazards functions using data from people with T2DM registered in the Swedish National Diabetes Registry (n = 389 366). Competing outcomes were (i) CVD events (vascular mortality, myocardial infarction, or stroke) and (ii) non-vascular mortality. Predictors were age, sex, smoking, systolic blood pressure, body mass index, haemoglobin A1c, estimated glomerular filtration rate, non- high-density lipoprotein cholesterol, albuminuria, T2DM duration, insulin treatment, and history of CVD. External validation was performed using data from the ADVANCE, ACCORD, ASCOT and ALLHAT-LLT-trials, the SMART and EPIC-NL cohorts, and the Scottish diabetes register (total n = 197 785). Predicted and observed CVD-free survival showed good agreement in all validation sets. C-statistics for prediction of CVD were 0.83 (95% confidence interval: 0.83-0.84) and 0.64-0.65 for internal and external validation, respectively. We provide an interactive calculator at www.U-Prevent.com that combines model predictions with relative treatment effects from trials to predict individual benefit from preventive treatment. CONCLUSION: Cardiovascular disease-free life expectancy and effects of lifelong prevention in terms of CVD-free life-years gained can be estimated for people with T2DM using readily available clinical characteristics. Predictions of individual-level treatment effects facilitate translation of trial results to individual patients.

Trends in incidence and case fatality of acute myocardial infarction, angina and coronary revascularisation in people with and without type 2 diabetes in Scotland between 2006 and 2015.

AIMS/HYPOTHESIS: The aim of the study was to examine trends in the incidence and case fatality of acute myocardial infarction (AMI) and in hospital admissions for angina and coronary revascularisation procedures in people with type 2 diabetes and in people without diabetes in Scotland between 2006 and 2015. METHODS: In this retrospective cohort study, AMI, angina and revascularisation event data were obtained for adults from hospital admissions and death records linked to a population-based diabetes register. Incidence by diabetes status was estimated using negative binomial models with adjustment or stratification by age, sex, deprivation and calendar year. Logistic regression was used to estimate AMI case fatality by diabetes status. RESULTS: There were 129,926 incident AMI events, 41,263 angina admissions and 69,875 coronary revascularisation procedures carried out during 34.9 million person-years of follow-up. The adjusted incidence of AMI, angina and revascularisation procedures declined by 2.0% (95% CI 1.73%, 2.26%), 9.62% (95% CI 9.22%, 10.01%) and 0.35% (95% CI -0.09%, 0.79%) per year, respectively. The rate of decline did not differ materially by diabetes status. RRs of AMI for type 2 diabetes were 1.86 (95% CI 1.74, 1.98) for men and 2.32 (95% CI 2.15, 2.51) for women. Of the 77,211 people admitted to hospital with a first AMI, 7842 (10.2%) died within 30 days of admission. Case fatality was higher in people with type 2 diabetes than in people without diabetes and declined in both groups by 7.93% (95% CI 7.03%, 8.82%) per year. CONCLUSIONS/INTERPRETATION: The incidence of AMI, angina, revascularisation and AMI case fatality has declined over time, but the increased risk associated with type 2 diabetes has remained approximately constant.

Incidence of Hospitalization for Heart Failure and Case-Fatality Among 3.25 Million People With and Without Diabetes Mellitus.

BACKGROUND: Recent clinical trials of new glucose-lowering treatments have drawn attention to the importance of hospitalization for heart failure as a complication of diabetes mellitus. However, the epidemiology is not well described, particularly for type 1 diabetes mellitus. We examined the incidence and case-fatality of heart failure hospitalizations in the entire population aged ≥30 years resident in Scotland during 2004 to 2013. METHODS: Date and type of diabetes mellitus diagnosis were linked to heart failure hospitalizations and deaths using the national Scottish registers. Incidence rates and case-fatality were estimated in regression models (quasi-Poisson and logistic regression respectively). All estimates are adjusted for age, sex, socioeconomic status, and calendar-year. RESULTS: Over the 10-year period of the study, among 3.25 million people there were 91, 429, 22 959, and 1313 incident heart failure events among those without diabetes mellitus, with type 2, and type 1 diabetes mellitus, respectively. The crude incidence rates of heart failure hospitalization were therefore 2.4, 12.4, and 5.6 per 1000 person-years for these 3 groups. Heart failure hospitalization incidence was higher in people with diabetes mellitus, regardless of type, than in people without. Relative differences were smallest for older men, in whom the difference was nonetheless large (men aged 80, rate ratio 1.78; 95% CI, 1.45-2.19). Rates declined similarly, by 0.2% per calendar-year, in people with type 2 diabetes mellitus and without diabetes mellitus. Rates fell faster, however, in those with type 1 diabetes mellitus (2.2% per calendar-year, rate ratio for type 1/calendar-year interaction 0.978; 95% CI, 0.959-0.998). Thirty-day case-fatality was similar among people with type 2 diabetes mellitus and without diabetes mellitus, but was higher in type 1 diabetes mellitus for men (odds ratio, 0.96; 95% CI, 0.95-0.96) and women (odds ratio, 0.98; 95% CI, 0.97-0.98). Case-fatality declined over time for all groups (3.3% per calendar-year, odds ratio per calendar-year 0.967; 95% CI, 0.961-0.973). CONCLUSIONS: Despite falling incidence, particularly in type 1 diabetes mellitus, heart failure remains ≈2-fold higher than in people without diabetes mellitus, with higher case-fatality in those with type 1 diabetes mellitus. These findings support the view that heart failure is an under-recognized and important complication in diabetes mellitus, particularly for type 1 disease.

Measuring the Association Between Body Mass Index and All-Cause Mortality in the Presence of Missing Data: Analyses From the Scottish National Diabetes Register.

Incorrectly handling missing data can lead to imprecise and biased estimates. We describe the effect of applying different approaches to handling missing data in an analysis of the association between body mass index and all-cause mortality among people with type 2 diabetes. We used data from the Scottish diabetes register that were linked to hospital admissions data and death registrations. The analysis was based on people diagnosed with type 2 diabetes between 2004 and 2011, with follow-up until May 31, 2014. The association between body mass index and mortality was investigated using Cox proportional hazards models. Findings were compared using 4 different missing-data methods: complete-case analysis, 2 multiple-imputation models, and nearest-neighbor imputation. There were 124,451 cases of type 2 diabetes, among which there were 17,085 deaths during 787,275 person-years of follow-up. Patients with missing data (24.8%) had higher mortality than those without missing data (adjusted hazard ratio = 1.36, 95% confidence interval: 1.31, 1.41). A U-shaped relationship between body mass index and mortality was observed, with the lowest hazard ratios occurring among moderately obese people, regardless of the chosen approach for handling missing data. Missing data may affect absolute and relative risk estimates differently and should be considered in analyses of routinely collected data.

Trends in type 2 diabetes incidence and mortality in Scotland between 2004 and 2013.

AIMS/HYPOTHESIS: The relative contribution of increasing incidence and declining mortality to increasing prevalence of type 2 diabetes in Scotland is unclear. Trends in incidence and mortality rates are described for type 2 diabetes in Scotland between 2004 and 2013 by age, sex and socioeconomic deprivation. METHODS: Data for incident and prevalent cases of type 2 diabetes were obtained from the Scottish national diabetes register with number of deaths identified from linkage to mortality records. Population size and death data for Scotland by age, sex and socioeconomic deprivation were obtained from National Records of Scotland. Age- and sex-specific incidence and mortality rates stratified by year and deciles of socioeconomic status were calculated using Poisson models. RESULTS: There were 180,290 incident cases of type 2 diabetes in Scotland between 2004 and 2013. Overall, incidence of type 2 diabetes remained stable over time and was 4.88 (95% CI 4.84, 4.90) and 3.33 (3.28, 3.32) per 1000 in men and women, respectively. However, incidence increased among young men, remained stable in young women, and declined in older men and women. Incidence rates declined in all socioeconomic groups but increased after 2008 in the most deprived groups. Standardised mortality ratios associated with diabetes, adjusted for age and socioeconomic group, were 1.38 (1.36, 1.41) in men and 1.49 (1.45, 1.52) in women, and remained constant over time. CONCLUSIONS/INTERPRETATION: Incidence of type 2 diabetes has stabilised in recent years suggesting that increasing prevalence may be primarily attributed to declining mortality. Prevention of type 2 diabetes remains important, particularly among socioeconomically deprived populations.

Cancer incidence in persons with type 1 diabetes: a five-country study of 9,000 cancers in type 1 diabetic individuals.

AIMS/HYPOTHESIS: An excess cancer incidence of 20-25% has been identified among persons with diabetes, most of whom have type 2 diabetes. We aimed to describe the association between type 1 diabetes and cancer incidence. METHODS: Persons with type 1 diabetes were identified from five nationwide diabetes registers: Australia (2000-2008), Denmark (1995-2014), Finland (1972-2012), Scotland (1995-2012) and Sweden (1987-2012). Linkage to national cancer registries provided the numbers of incident cancers in people with type 1 diabetes and in the general population. We used Poisson models with adjustment for age and date of follow up to estimate hazard ratios for total and site-specific cancers. RESULTS: A total of 9,149 cancers occurred among persons with type 1 diabetes in 3.9 million person-years. The median age at cancer diagnosis was 51.1 years (interquartile range 43.5-59.5). The hazard ratios (HRs) (95% CIs) associated with type 1 diabetes for all cancers combined were 1.01 (0.98, 1.04) among men and 1.07 (1.04, 1.10) among women. HRs were increased for cancer of the stomach (men, HR 1.23 [1.04, 1.46]; women, HR 1.78 [1.49, 2.13]), liver (men, HR 2.00 [1.67, 2.40]; women, HR 1.55 [1.14, 2.10]), pancreas (men, HR 1.53 [1.30, 1.79]; women, HR 1.25 [1.02,1.53]), endometrium (HR 1.42 [1.27, 1.58]) and kidney (men, HR 1.30 [1.12, 1.49]; women, HR 1.47 [1.23, 1.77]). Reduced HRs were found for cancer of the prostate (HR 0.56 [0.51, 0.61]) and breast (HR 0.90 [0.85, 0.94]). HRs declined with increasing diabetes duration. CONCLUSION: Type 1 diabetes was associated with differences in the risk of several common cancers; the strength of these associations varied with the duration of diabetes.

Association of a calcium channel blocker and diuretic prescribing cascade with adverse events: A population-based cohort study.

BACKGROUND: Prescribing cascades occur when a drug adverse event is misinterpreted as a new medical condition and a second, potentially unnecessary drug, is prescribed to treat the adverse event. The population-level consequences of prescribing cascades remain unknown. METHODS: This population-based cohort study used linked health administrative databases in Ontario, Canada. The study included community-dwelling adults, 66 years of age or older with hypertension and no history of heart failure (HF) or diuretic use in the prior year, newly dispensed a calcium channel blocker (CCB). Individuals subsequently dispensed a diuretic within 90 days of incident CCB dispensing were classified as the prescribing cascade group, and compared to those not dispensed a diuretic, classified as the non-prescribing cascade group. Those with and without a prescribing cascade were matched one-to-one on the propensity score and sex. The primary outcome was a serious adverse event (SAE), which was the composite of emergency room visits and hospitalizations in the 90-day follow-up period. We estimated hazard ratios (HRs) with 95% confidence intervals (CI) for SAE using an Andersen-Gill recurrent events regression model. RESULTS: Among 39,347 older adults with hypertension and no history of HF who were newly dispensed a CCB, 1881 (4.8%) had a new diuretic dispensed within 90 days after CCB initiation. Compared to the non-prescribing cascade group, those in the prescribing cascade group had higher rates of SAEs (HR: 1.21, 95% CI: 1.02-1.43). CONCLUSIONS: The CCB-diuretic prescribing cascade was associated with an increased rate of SAEs, suggesting harm beyond prescribing a second drug therapy. Our study raises awareness of the downstream impact of the CCB-diuretic prescribing cascade at a population level and provides an opportunity for clinicians who identify this prescribing cascade to review their patients' medications to determine if they can be optimized.

Remdesivir Is Associated With Reduced Mortality in COVID-19 Patients Requiring Supplemental Oxygen Including Invasive Mechanical Ventilation Across SARS-CoV-2 Variants.

Background: This comparative effectiveness study investigated the effect of remdesivir on in-hospital mortality among patients hospitalized for coronavirus disease 2019 (COVID-19) requiring supplemental oxygen including low-flow oxygen (LFO), high-flow oxygen/noninvasive ventilation (HFO/NIV), or invasive mechanical ventilation/extracorporeal membrane oxygenation (IMV/ECMO) across variant of concern (VOC) periods. Methods: Patients hospitalized for COVID-19 between December 2020 and April 2022 and administered remdesivir upon admission were 1:1 propensity score matched to patients not administered remdesivir during their COVID-19 hospitalization. Analyses were stratified by supplemental oxygen requirement upon admission and VOC period. Cox proportional hazards models were used to derive adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for 14- and 28-day mortality. Results: Patients treated with remdesivir (67 582 LFO, 34 857 HFO/NIV, and 4164 IMV/ECMO) were matched to non-remdesivir patients. Unadjusted mortality rates were significantly lower for remdesivir-treated patients at 14 days (LFO: 6.4% vs. 8.8%; HFO/NIV: 16.8% vs. 19.4%; IMV/ECMO: 27.8% vs. 35.3%) and 28 days (LFO: 9.8% vs. 12.3%; HFO/NIV: 25.8% vs. 28.3%; IMV/ECMO: 41.4% vs. 50.6%). After adjustment, remdesivir treatment was associated with a statistically significant reduction in in-hospital mortality at 14 days (LFO: aHR, 0.72; 95% CI, 0.66-0.79; HFO/NIV: aHR, 0.83; 95% CI, 0.77-0.89; IMV/ECMO: aHR, 0.73; 95% CI, 0.65-0.82) and 28 days (LFO: aHR, 0.79; 95% CI, 0.73-0.85; HFO/NIV: aHR, 0.88; 95% CI, 0.82-0.93; IMV/ECMO: aHR, 0.74; 95% CI, 0.67-0.82) compared with non-remdesivir treatment. Lower risk of mortality among remdesivir-treated patients was observed across VOC periods. Conclusions: Remdesivir treatment is associated with significantly reduced mortality among patients hospitalized for COVID-19 requiring supplemental oxygen upon admission, including those requiring HFO/NIV or IMV/ECMO with severe or critical disease, across VOC periods.

Estimating individual lifetime risk of incident cardiovascular events in adults with Type 2 diabetes: an update and geographical calibration of the DIAbetes Lifetime perspective model (DIAL2).

AIMS: The 2021 European Society of Cardiology cardiovascular disease (CVD) prevention guidelines recommend the use of (lifetime) risk prediction models to aid decisions regarding intensified preventive treatment options in adults with Type 2 diabetes, e.g. the DIAbetes Lifetime perspective model (DIAL model). The aim of this study was to update the DIAL model using contemporary and representative registry data (DIAL2) and to systematically calibrate the model for use in other European countries. METHODS AND RESULTS: The DIAL2 model was derived in 467 856 people with Type 2 diabetes without a history of CVD from the Swedish National Diabetes Register, with a median follow-up of 7.3 years (interquartile range: 4.0-10.6 years) and comprising 63 824 CVD (including fatal CVD, non-fatal stroke and non-fatal myocardial infarction) events and 66 048 non-CVD mortality events. The model was systematically recalibrated to Europe's low- and moderate-risk regions using contemporary incidence data and mean risk factor distributions. The recalibrated DIAL2 model was externally validated in 218 267 individuals with Type 2 diabetes from the Scottish Care Information-Diabetes (SCID) and Clinical Practice Research Datalink (CPRD). In these individuals, 43 074 CVD events and 27 115 non-CVD fatal events were observed. The DIAL2 model discriminated well, with C-indices of 0.732 [95% confidence interval (CI) 0.726-0.739] in CPRD and 0.700 (95% CI 0.691-0.709) in SCID. CONCLUSION: The recalibrated DIAL2 model provides a useful tool for the prediction of CVD-free life expectancy and lifetime CVD risk for people with Type 2 diabetes without previous CVD in the European low- and moderate-risk regions. These long-term individualized measures of CVD risk are well suited for shared decision-making in clinical practice as recommended by the 2021 CVD ESC prevention guidelines.