Diabetes-related risk factors and survival among individuals with type 2 diabetes and breast, lung, colorectal, or prostate cancer.

Premature death in diabetes is increasingly caused by cancer. The objectives were to estimate the excess mortality when individuals with type 2 diabetes(T2D) were diagnosed with cancer, and to examine the impact of modifiable diabetes-related risk factors. This longitudinal nationwide cohort study included individuals with T2D registered in the Swedish National Diabetes Register between 1998-2019. Poisson models were used to estimate mortality as a function of time-updated risk-factors, adjusted for sex, age, diabetes duration, marital status, country of birth, BMI, blood pressure, lipids, albuminuria, smoking, and physical activity. We included 690,539 individuals with T2D and during 4,787,326 person-years of follow-up 179,627 individuals died. Overall, the all-cause mortality rate ratio was 3.75 [95%confidence interval(CI):3.69-3.81] for individuals with T2D and cancer compared to those remaining free of cancer. The most marked risk factors associated to mortality among individuals with T2D and cancer were low physical activity, 1.59 (1.57-1.61) and smoking, 2.15 (2.08-2.22), whereas HbA1c, lipids, hypertension, and BMI had no/weak associations with survival. In a future with more patients with comorbid T2D and cancer diagnoses, these results suggest that smoking and physical activity might be the two most salient modifiable risk factors for mortality in people with type 2 diabetes and cancer.

Glucagon-like peptide-1 receptor agonists use and associations with outcomes in heart failure and type 2 diabetes. Data from the Swedish Heart Failure and Swedish National Diabetes Registries.

AIMS: To assess use and associations with outcomes of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in a real-world population with heart failure (HF) and type 2 diabetes (T2DM). METHODS AND RESULTS: The Swedish HF Registry was linked with the National Diabetes Registry and other national registries. Independent predictors of GLP-1 RA use were assessed by multivariable logistic regressions, and associations with outcomes by Cox regressions in a 1:1 propensity score-matched cohort. Of 8188 patients enrolled in 2017-2021, 9% received a GLP-1 RA. Independent predictors of GLP-1 RA use were age<75, worse glycaemic control, impaired renal function, obesity and reduced ejection fraction (EF). GLP-1 RA use was not significantly associated with a composite of HF hospitalization (HHF) or cardiovascular (CV) death regardless of EF, but was associated with lower risk of major adverse CV events (CV death, non-fatal stroke/transient ischemic attack or myocardial infarction), CV and all-cause death. In patients with body mass index≥30 kg/m2, GLP-1 RA use was also associated with lower risk of HHF/CV death and HHF alone. CONCLUSIONS: In patients with HF and T2DM, GLP-1 RA use was independently associated with more severe T2DM, reduced EF and obesity, and was not associated with a higher risk of HHF/CV death but with longer survival and less major CV adverse events. An association with lower HHF/CV death and HHF was observed in obese patients. Our findings provide new insights into GLP-1 RA use and its safety in HF and T2DM.

Risk factors for and risk of all-cause and atherosclerotic cardiovascular disease mortality in people with type 2 diabetes and peripheral artery disease: an observational, register-based cohort study.

BACKGROUND: Type 2 diabetes (T2D) and peripheral artery disease (PAD) are recognized as independent risk factors contributing to excess mortality. Contemporary observational studies exploring the associations of risk factors, and risk of all-cause and atherosclerotic cardiovascular disease mortality in persons with T2D following the onset of incident peripheral artery disease are limited. The objectives of this study were to investigate the associations of risk factors, and assess mortality risks in people with T2D compared with controls without T2D after the onset of PAD. METHODS: All persons with T2D (n = 150,215) registered in the Swedish National Diabetes Register between 2005 and 2009 were included, along with 346,423 controls without T2D matched for sex and age. Data were retrieved from several national registries, capturing information on risk factors, onset of incident peripheral artery disease, other comorbidities, socioeconomic factors, and outcomes. To compare persons with T2D and controls following the onset of peripheral artery disease regarding the risk of all-cause, and atherosclerotic cardiovascular disease mortality, Cox proportional hazard models and Kaplan-Meier curves were employed. A gradient-boosting model was utilized to estimate the relative statistical contribution of risk factors to the modeling of incident mortality risk in people with both T2D and peripheral artery disease. RESULTS: Crude rates of incident all-cause mortality were higher in individuals with T2D compared with controls, following the onset of PAD (600.4 (95% CI, 581.4-619.8) per 10,000 person-years versus 549.1 (95% CI, 532.1-566.5) per 10,000 person-years). Persons with T2D had an adjusted hazard ratio (HR) for all-cause mortality of 1.12 (95% CI, 1.05-1.19, P < 0.01) compared with controls after onset of incident PAD. The comparable adjusted HR for cardiovascular mortality was 1.13 (95% CI, 1.07-1.19, P < 0.01). High age and hyperglycemia at baseline played a significant role in contributing to the predictive models for incident all-cause and cardiovascular mortality among individuals with both T2D and PAD. CONCLUSIONS: The presence of T2D with concomitant PAD is related to an increased risk of both all-cause and cardiovascular mortality compared with individuals with only PAD. This argues for implementing optimized and intensive treatment strategies for individuals with both conditions.

Glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer: Scandinavian cohort study.

OBJECTIVE: To investigate whether use of glucagon-like peptide 1 (GLP1) receptor agonists is associated with increased risk of thyroid cancer. DESIGN: Scandinavian cohort study. SETTING: Denmark, Norway, and Sweden, 2007-21. PARTICIPANTS: Patients who started GLP1 receptor agonist treatment were compared with patients who started dipeptidyl peptidase 4 (DPP4) inhibitor treatment, and in an additional analysis, patients who started sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment. MAIN OUTCOME MEASURES: Thyroid cancer identified from nationwide cancer registers. An active-comparator new user study design was used to minimise risks of confounding and time related biases from using real world studies of drug effects. Cox regression was used to estimate hazard ratios, controlling for potential confounders with propensity score weighting. RESULTS: The mean follow-up time was 3.9 years (standard deviation 3.5 years) in the GLP1 receptor agonist group and 5.4 years (standard deviation 3.5 years) in the DPP4 inhibitor group. 76 of 145 410 patients (incidence rate 1.33 events per 10 000 person years) treated with GLP1 receptor agonists and 184 of 291 667 patients (incidence rate 1.46 events per 10 000 person years) treated with DPP4 inhibitors developed thyroid cancer. GLP1 receptor agonist use was not associated with increased risk of thyroid cancer (hazard ratio 0.93, 95% confidence interval 0.66 to 1.31; rate difference -0.13, 95% confidence interval -0.61 to 0.36 events per 10 000 person years). The hazard ratio for medullary thyroid cancer was 1.19 (0.37 to 3.86). In the additional analysis comparing the GLP1 receptor agonist group with the SGLT2 inhibitor group, the hazard ratio for thyroid cancer was 1.16 (0.65 to 2.05). CONCLUSIONS: In this large cohort study using nationwide data from three countries, GLP1 receptor agonist use was not associated with a substantially increased risk of thyroid cancer over a mean follow-up of 3.9 years. In the main analysis comparing GLP1 receptor agonists with DPP4 inhibitors, the upper limit of the confidence interval was consistent with no more than a 31% increase in relative risk.

Metabolic Syndrome Traits Increase the Risk of Major Adverse Liver Outcomes in Type 2 Diabetes.

OBJECTIVE: Type 2 diabetes (T2D) increases the risk for major adverse liver outcomes (MALOs), including cirrhosis and its complications. Patients with T2D frequently have other traits of the metabolic syndrome (MetS). It remains uncertain whether there is a synergistic effect of accumulating MetS traits on future MALO risk. RESEARCH DESIGN AND METHODS: Patients with T2D without a history of liver disease were identified from national registers in Sweden from 1998 to 2021. MetS traits included hypertension, low HDL level, hypertriglyceridemia, obesity, and albuminuria, in addition to T2D. MALO events were identified based on administrative coding from national registers until 31 October 2022. Data were analyzed using Cox regression models. RESULTS: In total, 230,992 patients were identified (median age 64 years; 58% male), of whom 3,215 (1.39%) developed MALOs over a median follow-up of 9.9 years. Compared with patients with one MetS trait (only T2D) at baseline, those with more than one MetS trait had a higher rate of MALOs (adjusted hazard ratio [aHR] 2.33, 95% CI 1.53-3.54). The rate of MALOs increased progressively with increasing numbers of MetS traits at baseline (aHR 1.28 per added trait, 95% CI 1.23-1.33). During follow-up, patients who acquired additional MetS traits had a progressively higher rate of MALOs. The MetS trait with the largest association with incident MALOs was hypertension (aHR 2.06, 95% CI 1.57-2.71). CONCLUSIONS: Having or acquiring additional traits of MetS increase the rate of progression to MALOs in patients with T2D. These results could be used to inform screening initiatives for liver disease.

Assisting the implementation of screening for type 1 diabetes by using artificial intelligence on publicly available data.

The type 1 diabetes community is coalescing around the benefits and advantages of early screening for disease risk. To be accepted by healthcare providers, regulatory authorities and payers, screening programmes need to show that the testing variables allow accurate risk prediction and that individualised risk-informed monitoring plans are established, as well as operational feasibility, cost-effectiveness and acceptance at population level. Artificial intelligence (AI) has the potential to contribute to solving these issues, starting with the identification and stratification of at-risk individuals. ASSET (AI for Sustainable Prevention of Autoimmunity in the Society; www.asset.healthcare ) is a public/private consortium that was established to contribute to research around screening for type 1 diabetes and particularly to how AI can drive the implementation of a precision medicine approach to disease prevention. ASSET will additionally focus on issues pertaining to operational implementation of screening. The authors of this article, researchers and clinicians active in the field of type 1 diabetes, met in an open forum to independently debate key issues around screening for type 1 diabetes and to advise ASSET. The potential use of AI in the analysis of longitudinal data from observational cohort studies to inform the design of improved, more individualised screening programmes was also discussed. A key issue was whether AI would allow the research community and industry to capitalise on large publicly available data repositories to design screening programmes that allow the early detection of individuals at high risk and enable clinical evaluation of preventive therapies. Overall, AI has the potential to revolutionise type 1 diabetes screening, in particular to help identify individuals who are at increased risk of disease and aid in the design of appropriate follow-up plans. We hope that this initiative will stimulate further research on this very timely topic.

Implantable cardioverter defibrillator and cardiac resynchronization treatment in people with type 2 diabetes: a comparison with age- and sex matched controls from the general population.

BACKGROUND: Increased risk of severe tachyarrhythmias is reported in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to explore if treatment with cardiac implantable electronic device (CIED) such as implantable cardioverter defibrillator (ICD), cardiac resynchronization therapy- pacemaker and -defibrillator (CRT-P/CRT-D) differed in patients with vs. without T2DM. A secondary aim was to identify patient characteristics indicating an increased CIED treatment. METHOD: 416 162 adult patients with T2DM from the Swedish National Diabetes Registry and 2 081 087 controls from the Swedish population, matched for age, sex and living area, were included between 1/1/1998 and 31/12/2012 and followed until 31/12/2013. They were compared regarding prevalence of ventricular tachycardia (VT) at baseline and the risk of receiving a CIED during follow-up. Multivariable Cox regression analysis was performed to estimate the risk of CIED-treatment and factors identifying patients with such risk. RESULTS: Ventricular fibrillation (VF) (0.1% vs 0.0004%) and (VT) (0.2% vs. 0.1%) were more frequent among patients with T2DM compared to controls. CIED-treatment was significantly increased in patients with T2DM both in unadjusted and adjusted analyses. HR and 95% CI, after adjustment for sex, age, marital status, income, education, country of birth, coronary artery disease and congestive heart failure, were 1.32 [1.21-1.45] for ICD, 1.74 [1.55-1.95] for CRT-P and 1.69 [1.43-1.99] for CRT-D. Blood-pressure and lipid lowering therapies were independent risk factors associated to receiving CIED, while female sex was protective. CONCLUSIONS: Although the proportion of VT/VF was low, patients with T2DM had a higher prevalence of these conditions and increased risk for treatment with CIED compared to controls. This underlines the importance of recognizing that T2DM patients have an increased need of CIED.

Risk Factors for and Risk of Peripheral Artery Disease in Swedish Individuals With Type 2 Diabetes: A Nationwide Register-Based Study.

OBJECTIVE: To investigate to what extent having control of peripheral artery disease (PAD) risk factors is associated with the risk of incident PAD in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 148,096 individuals with type 2 diabetes in the Swedish National Diabetes Register between 2005 and 2009 were included and matched with 320,066 control subjects on the basis of age, sex, and county. A few control subjects who developed type 2 diabetes after recruitment, during wash-in (<0.2%), were not censored but instead matched with two new control subjects. Individuals with type 2 diabetes were evaluated according to the number of PAD risk factors beyond recommended guideline levels at baseline, including LDL cholesterol, blood pressure, smoking, glycated hemoglobin, and estimated glomerular filtration rate. Incident PAD events were ascertained from 2006 to 2019. RESULTS: A graded association was observed between the number of PAD risk factors not at target and incident PAD in individuals with type 2 diabetes. The adjusted hazard ratio for PAD was 1.41 (95% CI 1.23-1.63) for those with type 2 diabetes with all PAD risk factors within target compared with control subjects matched for sex, age, and county but not risk factor status, in contrast with 9.28 (95% CI 3.62-23.79) for those with all five PAD risk factors not at target. CONCLUSIONS: A graded association was observed between increasing number of PAD risk factors not at target and incident PAD in individuals with type 2 diabetes.

Association of glucagon-like peptide-1 receptor agonists with serious liver events among patients with type 2 diabetes: A Scandinavian cohort study.

BACKGROUND AND AIMS: Clinical trials suggest that glucagon-like peptide-1 (GLP-1) receptor agonists may have beneficial effects on NAFLD, but the impact on hard hepatic end points is unknown. We assessed the association between the use of GLP-1 receptor agonists and the risk of serious liver events in routine clinical practice. APPROACH AND RESULTS: Cohort study using data from nationwide registers in Sweden, Denmark, and Norway, 2007-2020, including 91,479 initiators of GLP-1 receptor agonists and 244,004 initiators of the active comparator, dipeptidyl peptidase-4 inhibitors, without a history of chronic liver disease other than NAFLD/NASH. The primary outcome was serious liver events: a composite of incident compensated and decompensated cirrhosis and HCC. Secondary outcomes were the individual components of the primary outcome. Cox regression was used to estimate HRs, using propensity score weighting to control for confounding. Users of GLP-1 receptor agonists had 608 serious liver events (adjusted incidence rate: 16.9 events per 10,000 person-years), compared with 1770 events among users of dipeptidyl peptidase-4 inhibitors (19.2 events per 10,000 person-years). The adjusted HR was 0.85 (95% CI: 0.75 to 0.97), and the rate difference was -2.1 (-4.4 to 0.1) events per 10,000 person-years. In secondary outcome analyses, the adjusted HR was 0.85 (0.75 to 0.97) for compensated and decompensated cirrhosis and 1.05 (0.80 to 1.39) for HCC. CONCLUSIONS: The use of GLP-1 receptor agonists was associated with a significantly reduced risk of serious liver events, driven by a reduction of compensated and decompensated cirrhosis.

The correlation between small papillary thyroid cancers and gamma radionuclides Cs-137, Th-232, U-238 and K-40 using spatially-explicit, register-based methods.

A steep increase of small papillary thyroid cancers (sPTCs) has been observed globally. A major risk factor for developing PTC is ionizing radiation. The aim of this study is to investigate the spatial distribution of sPTC in Sweden and the extent to which prevalence is correlated to gamma radiation levels (Caesium-137 (Cs-137), Thorium-232 (Th-232), Uranium-238 (U-238) and Potassium-40 (K-40)) using multiple geospatial and geostatistical methods. The prevalence of metastatic sPTC was associated with significantly higher levels of Gamma radiation from Th-232, U-238 and K-40. The association is, however, inconsistent and the prevalence is higher in densely populated areas. The results clearly indicate that sPTC has causative factors that are neither evenly distributed among the population, nor geographically, calling for further studies with bigger cohorts. Environmental factors are believed to play a major role in the pathogenesis of the disease.

Psychotropic Medication Use in Children and Adolescents With Type 1 Diabetes.

Importance: Children and adolescents with type 1 diabetes (T1D) face elevated risks of psychiatric disorders. Despite their nonnegligible adverse effects, psychotropic medications are a common cost-effective approach to alleviating psychiatric symptoms, but evidence regarding their dispensation to children and adolescents with T1D remains lacking. Objective: To examine the trends and patterns of psychotropic medication dispensation among children and adolescents with T1D in Sweden between 2006 and 2019. Design, Setting, and Participants: This cohort study used data from multiple Swedish registers. The main study cohort included children and adolescents residing in Sweden from 2006 to 2019 and was followed up until the earliest of December 31, 2019, 18th birthday, emigration, or death. Data analyses were conducted from November 1, 2022, to April 30, 2023. Exposures: Type 1 diabetes. Main Outcomes and Measures: The primary outcomes were trends and patterns of psychotropic medication dispensation (including antipsychotics, antidepressants, anxiolytics, hypnotics, mood stabilizers, and medications for attention-deficit/hyperactivity disorder [ADHD]), psychotropic medication initiation, and history of neurodevelopmental and psychiatric diagnosis. Cumulative incidence curves and Cox proportional hazard models were used to estimate the aggregated incidence and hazard ratios of medication initiation after diabetes onset. Results: Of 3 723 745 children and adolescents (1 896 199 boys [50.9%]), 13 200 (0.4%; 7242 boys [54.9%]) had T1D (median [IQR] age at diagnosis, 11.1 [7.6-14.7] years). Between 2006 and 2019, psychotropic medication dispensation increased from 0.85% (95% CI, 0.65%-1.10%) to 3.84% (3.11%-4.69%) among children and from 2.72% (95% CI, 2.15%-3.39%) to 13.54% (95% CI, 12.88%-14.23%) among adolescents with T1D, consistently higher than their peers without T1D. The most commonly dispensed medications included hypnotics, ADHD medications, anxiolytics, and selective serotonin reuptake inhibitors, and all exhibited increasing trends. For those with T1D, psychiatric care was the primary prescription source, and up to 50.1% of treatments lasted more than 12 months. In addition, children and adolescents with T1D showed higher cumulative incidence and hazard ratios of medication initiation after diabetes onset than their same-age and same-sex counterparts. Conclusions and Relevance: This cohort study found an increasing trend in psychotropic medication dispensation among children and adolescents with T1D from 2006 to 2019, persistently higher than those without T1D. These findings call for further in-depth investigations into the benefits and risks of psychotropic medications within this population and highlight the importance of integrating pediatric diabetes care and mental health care for early detection of psychological needs and careful monitoring of medication use.

Use of DPP4 Inhibitors and GLP-1 Receptor Agonists and Risk of Intestinal Obstruction: Scandinavian Cohort Study.

BACKGROUND & AIMS: Concerns have been raised that the incretin-based diabetes drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists may increase the risk of intestinal obstruction. We aimed to assess the association between use of DPP4 inhibitors and GLP-1 receptor agonists and the risk of intestinal obstruction. METHODS: Using data from nationwide registers in Sweden, Denmark, and Norway, 2013-2021, we conducted 2 cohort studies, one for DPP4 inhibitors and one for GLP-1 receptor agonists, to investigate the risk of intestinal obstruction as compared with an active comparator drug class (sodium-glucose co-transporter 2 [SGLT2] inhibitors). RESULTS: Among 19,0321 new users of DPP4 inhibitors (median (interquartile range [IQR]) follow-up time, 1.3 [0.6-2.6] years) and 139,315 new users of SGLT2 inhibitors (median [IQR] follow-up time, 0.8 [0.4-1.7] years), 919 intestinal obstruction events occurred. Use of DPP4 inhibitors, as compared with SGLT2 inhibitors, was not associated with a statistically significant increase in risk of intestinal obstruction (adjusted incidence rate, 2.0 vs 1.8 per 1000 person-years; hazard ratio, 1.13; 95% confidence interval, 0.96-1.34). Among 121,254 new users of GLP-1 receptor agonists (median [standard deviation] follow-up time, 0.9 [0.4-1.9] years) and 185,027 new users of SGLT2 inhibitors (median [IQR] follow-up time, 0.8 [0.4-1.8] years), 557 intestinal obstruction events occurred. Use of GLP-1 receptor agonists was not associated with a statistically significant increase in risk of intestinal obstruction (adjusted incidence rate, 1.3 vs 1.6 per 1000 person-years; hazard ratio, 0.83; 95% confidence interval, 0.69-1.01). CONCLUSIONS: In this analysis of nationwide data from 3 countries, previous safety signals indicating an increased risk of intestinal obstruction with use of DPP4 inhibitors and GLP-1 receptor agonists were not confirmed.

Educational Outcomes in Children and Adolescents With Type 1 Diabetes and Psychiatric Disorders.

Importance: Research shows that children and adolescents with type 1 diabetes (T1D), compared with their peers without diabetes, have a greater risk of psychiatric disorders. However, no study has comprehensively examined whether having psychiatric disorders is associated with educational outcomes in children and adolescents with T1D. Objective: To investigate educational outcomes in children and adolescents with T1D with and without psychiatric disorders. Design, Setting, and Participants: This cohort study used data from multiple Swedish registers. The main study cohort included individuals born in Sweden between January 1, 1973, and December 31, 1997, who were followed up from birth through December 31, 2013. Data analyses were conducted from March 1 to June 30, 2022. Exposures: Type 1 diabetes and psychiatric disorders (including neurodevelopmental disorders, depression, anxiety disorders, eating disorders, bipolar disorder, psychotic disorder, and substance misuse) diagnosed before 16 years of age. Main Outcomes and Measures: Achieving educational milestones (completing compulsory school [primary and lower secondary education], being eligible to and finishing upper secondary school, and starting and finishing university) and compulsory school performances. Results: Of 2 454 862 individuals (51.3% male), 13 294 (0.5%; 53.9% male) were diagnosed with T1D (median [IQR] age at diagnosis, 9.5 [6.0-12.5] years), among whom 1012 (7.6%) also had at least 1 psychiatric disorder. Compared with healthy individuals (without T1D and psychiatric disorders), individuals with T1D alone had slightly lower odds of achieving the examined educational milestones. However, those with both T1D and any psychiatric disorder had much lower odds of achieving milestones, including completing compulsory school (odds ratio [OR], 0.17; 95% CI, 0.13-0.21), being eligible for (OR, 0.25; 95% CI, 0.21-0.30) and finishing (OR, 0.19; 95% CI, 0.14-0.26) upper secondary school, and starting (OR, 0.36; 95% CI, 0.29-0.46) and finishing (OR, 0.30; 95% CI, 0.20-0.47) university. They also showed lower grade point averages for compulsory school subjects. These findings remained similar in sibling comparison analyses, suggesting independence from familial confounding. Conclusions and Relevance: In this cohort study of Swedish-born children and adolescents, those with T1D alone had minor difficulties with their educational outcomes, whereas those with both T1D and psychiatric disorders had universal long-term educational underachievement. These findings highlight the importance of identifying psychiatric disorders in pediatric patients with T1D and the need for targeted educational intervention and support to minimize the education gap between the affected children and their peers.

Risk factor variability and cardiovascular risk among patients with diabetes: a nationwide observational study.

AIMS: Cardiovascular risk factor control fluctuates, tends to change over time, and is potentially impacted by multifactorial interactions. Currently, the presence of risk factors, rather than their variability or interplay with one another, is taken into account to define the population at risk. The association between variability of risk factors and cardiovascular morbidity and mortality risk among patients with Type 2 diabetes mellitus (T2DM) remains debatable. METHODS AND RESULTS: Using registry-derived data, we identified 29 471 people with T2DM, without cardiovascular disease (CVD) at baseline, and with at least five measurements of risk factors. Variability for each variable was expressed as quartiles of the standard deviation during 3 years (exposure). The incidence of myocardial infarction, stroke, and all-cause mortality was assessed during 4.80 (2.40-6.70) years following the exposure phase. The association between the measures of variability and the risk of developing the outcome was investigated through multivariable Cox proportional-hazards regression analysis with stepwise variable selection. Then, the recursive partitioning and amalgamation (RECPAM) algorithm was used to explore the interaction among the variability of risk factors associated with the outcome. An association between the variability of HbA1c, body weight, systolic blood pressure, and total cholesterol with the outcome considered was found. Among the six classes of risk identified by RECPAM, patients with a high variability of both body weight and blood pressure had the highest risk [Class 6, hazard ratio (HR) = 1.81; 95% confidence interval (CI) 1.61-2.05] compared with patients with low variability of both body weight and total cholesterol (Class 1, reference), despite a progressive reduction in the mean level of risk factors during successive visits. Individuals with high weight variability but low-moderate systolic blood pressure variability (Class 5, HR = 1.57; 95% CI 1.28-1.68), patients with moderate/high weight variability associated with high/very high HbA1c variability (Class 4, HR = 1.33; 95% CI 1.20-1.49), subjects with moderate/high weight variability and with low/moderate HbA1c variability (Class 3, HR = 1.12; 95% CI 1.00-1.25), as well as those with low weight variability associated with high/very high total cholesterol variability (Class 2, HR = 1.14; 95% CI 1.00-1.30) also showed a significant increase in the risk of an event. CONCLUSION: Combined high variability of two risk factors, particularly body weight and blood pressure, is associated with cardiovascular risk among patients with T2DM. These findings highlight the importance of continuous balancing of multiple risk factors.

The variability of multiple risk factors is associated with an increased risk of cardiovascular events and mortality in patients with Type 2 diabetes. These variabilities interact with one another to identify classes of patients with an increased risk of having an event.Patients with a high variability of both body weight and systolic blood pressure had the greatest risk of cardiovascular diseases or mortality despite a progressive reduction in the mean level of risk factors.Individuals with high weight variability but low systolic blood pressure variability, patients with moderate/high weight variability associated with high HbA1c variability, subjects with moderate/high weight variability and with low/moderate HbA1c variability, as well as those with low weight variability but high total cholesterol variability also showed a significant increase in the risk of an event.

Sodium-Glucose Cotransporter 2 Inhibitor Treatment and Risk of Atrial Fibrillation: Scandinavian Cohort Study.

OBJECTIVE: To assess the association between use of sodium-glucose cotransporter 2 (SGLT2) inhibitors and the risk of new-onset atrial fibrillation (AF) in routine clinical practice. RESEARCH DESIGN AND METHODS: We used nationwide registers in Denmark, Norway, and Sweden from 2013 to 2018 in order to include patients without a history of AF who were newly prescribed an SGLT2 inhibitor or an active comparator (glucagon-like peptide 1 [GLP-1] receptor agonist). We performed a cohort study to assess new-onset AF in intention-to-treat analyses using Cox regression, adjusted for baseline covariates with propensity score weighting. RESULTS: We identified 79,343 new users of SGLT2 inhibitors (59.2% dapagliflozin, 40.0% empagliflozin, 0.8% canagliflozin, <0.1% ertugliflozin) and 57,613 new users of GLP-1 receptor agonists. Mean age of the study cohort was 61 years and 60% were men. The adjusted incidence rate of new-onset AF was 8.6 per 1,000 person-years for new users of SGLT2 inhibitors compared with 10.0 per 1,000 person-years for new users of GLP-1 receptor agonists. The adjusted hazard ratio (aHR) was 0.89 (95% CI 0.81-0.96), and the rate difference was 1.4 fewer events per 1,000 person-years (95% CI 0.6-2.1). Using an as-treated exposure definition, the aHR for new-onset AF was 0.87 (95% CI 0.76-0.99). No statistically significant heterogeneity of the aHRs was observed between subgroups of patients with and without a history of heart failure or major cardiovascular disease. CONCLUSIONS: In this cohort study using nationwide data from three countries, use of SGLT2 inhibitors, compared with GLP-1 receptor agonists, was associated with a modestly reduced risk of new-onset AF.

Shared etiology of type 1 diabetes and Hashimoto's thyroiditis: a population-based twin study.

Objective: Type 1 diabetes and Hashimoto's thyroiditis frequently cluster in individuals and in families, indicating shared origins. The objective of this study was to investigate familial co-aggregation of these diseases and to quantify shared genetic and environmental factors. Design: This study is a twin cohort study. Methods: National health registers were used to identify cases among 110 814 Swedish twins. Co-aggregation was calculated as risk ratios for type 1 diabetes among co-twins of individuals with Hashimoto's thyroiditis, and vice-versa. Variance explained by genetics (i.e. heritability), and the proportions thereof shared between the diseases, was estimated by contrasting associations in monozygotic and dizygotic twins using structural equation models. Results: Individuals with one disease were at a high risk for the other disease (adjusted risk ratio: 11.4 (95% CI: 8.5-15.3)). Co-aggregation was more common in monozygotic than in dizygotic pairs, with adjusted risk ratios of 7.0 (95% CI: 3.2-15.1) and 1.7 (95% CI: 0.7-4.1), respectively. Genetic effects shared across diseases accounted for 11% of the variance for type 1 diabetes and 9% of the variance for Hashimoto's thyroiditis, while environmental factors unique to individual twins, but shared across diseases, accounted for 10% of the variance for type 1 diabetes and 18% of the variance for Hashimoto's thyroiditis. Conclusions: Both genes and environment unique to individual twins contribute to considerable etiologic overlap between type 1 diabetes and Hashimoto's thyroiditis. These findings add to the current knowledge on the mechanisms behind autoimmune disease clustering and could guide future research aimed at identifying pathophysiological mechanisms and intervention targets.

Early-Onset Type 2 Diabetes and Mood, Anxiety, and Stress-Related Disorders: A Genetically Informative Register-Based Cohort Study.

OBJECTIVE: To assess the association and familial coaggregation between early-onset type 2 diabetes (diagnosed before age 45 years) and mood, anxiety, and stress-related disorders and estimate the contribution of genetic and environmental factors to their co-occurrence. RESEARCH DESIGN AND METHODS: This population-based cohort study included individuals born in Sweden during 1968-1998, from whom pairs of full siblings, half-siblings, and cousins were identified. Information on diagnoses of early-onset type 2 diabetes and mood (including unipolar depression and bipolar disorder), anxiety, and stress-related disorders was obtained from the National Patient Register. Logistic and Cox regression models were used to assess the phenotypic association and familial coaggregation between type 2 diabetes and psychiatric disorders. Quantitative genetic modeling was conducted in full and maternal half-sibling pairs to estimate the relative contributions of genetic and environmental factors to the association. RESULTS: Among a total of 3,061,192 individuals, 7,896 (0.3%) were diagnosed with early-onset type 2 diabetes. These individuals had higher risks of any diagnosis (odds ratio [OR] 3.62 [95% CI 3.44, 3.80]) and specific diagnosis of unipolar depression (3.97 [3.75, 4.22]), bipolar disorder (4.17 [3.68, 4.73]), anxiety (3.76 [3.54, 3.99]), and stress-related disorders (3.35 [3.11, 3.61]). Relatives of individuals with early-onset type 2 diabetes also had higher overall risks of the examined psychiatric disorders (ORs 1.03-1.57). These associations are largely explained by genetic factors (51-78%), with the rest explained by nonshared environmental factors. CONCLUSIONS: Our findings highlight the burden of mood, anxiety, and stress-related disorders in early-onset type 2 diabetes and demonstrate that shared familial liability may contribute to their co-occurrence, suggesting that in the future research investigators should aim to identify shared risk factors and ultimately refine preventive and intervention strategies.

Association and Familial Coaggregation of Childhood-Onset Type 1 Diabetes With Depression, Anxiety, and Stress-Related Disorders: A Population-Based Cohort Study.

OBJECTIVE: To estimate the association and familial coaggregation of childhood-onset type 1 diabetes with depression, anxiety, and stress-related disorders. RESEARCH DESIGN AND METHODS: This was a population-based cohort study with use of data from Swedish nationwide registers. A total of ∼3.5 million individuals born in Sweden 1973-2007 were linked to their biological parents, full siblings and half-siblings, and cousins. Cox models were used to estimate the association and familial coaggregation of type 1 diabetes with depression, anxiety, and stress-related disorders. RESULTS: Individuals diagnosed with childhood-onset type 1 diabetes (n = 20,005) were found to be at greater risks of all outcomes: any psychiatric diagnosis (adjusted hazard ratio [aHR] 1.66 [95% CI 1.59-1.72]) or specific diagnoses of depression (1.85 [1.76-1.94]), anxiety (1.41[1.33-1.50]), and stress-related disorders (1.75 [1.62-1.89]), as well as use of antidepressants or anxiolytics (1.30 [1.26-1.34]), compared with individuals without type 1 diabetes. Overall, relatives of individuals with type 1 diabetes were at elevated risks of developing these outcomes, with the highest risks seen in parents (aHRs 1.18-1.25), followed by full siblings (aHRs 1.05-1.20), and the magnitudes of risk estimates appear proportional to familial relatedness. CONCLUSIONS: These results support existing evidence that children and adolescents with type 1 diabetes are at greater risks of developing depression, anxiety, and stress-related disorders and indicate that shared familial factors might contribute to these elevated risks. Our findings highlight the need for psychological consulting for children and their families in diabetes care. Quantitative and molecular genetic studies are warranted to further understand the etiology of these psychiatric disorders in type 1 diabetes.

Childhood-onset type 1 diabetes and attention-deficit/hyperactivity disorder with educational attainment: A population-based sibling-comparison study.

AIM: To examine the association of childhood-onset type 1 diabetes (T1D) and attention-deficit/hyperactivity disorder (ADHD) with educational outcomes from compulsory school to university. METHODS: Using multiple Swedish nationwide registers, we followed up on 1,474,941 individuals born in Sweden from 1981-1995 to December 31, 2013. Associations of T1D and ADHD with achieving educational milestones (from compulsory school to university) and school performances were estimated using logistic and linear regression models and sibling comparison models. RESULTS: Compared to their peers, children with both T1D and ADHD were less likely to achieve any of the educational attainments, including completing compulsory school (adjusted OR [aOR] [95% CI]: 0.43 [0.26, 0.72]), be eligible to and finishing upper secondary school (0.26 [0.19, 0.36], 0.24 [0.17, 0.35], respectively), and starting university (0.38 [0.17, 0.90]). The odds of achieving these educational milestones were substantially lower in children with ADHD alone (aORs: 0.14-0.44), but were slightly worse or no differences in children with T1D alone (aORs: 0.86-1.08). All associations above remained similar in the sibling comparison models. CONCLUSION: Children and adolescents with both T1D and ADHD had long-term educational underachievement, with ADHD being the major contributor. Our findings suggest the importance of assessing ADHD in children with T1D and targeted support for minimising the education gap between the affected children and their peers.