Low birthweight in patients with type 2 diabetes is associated with elevated risk of cardiovascular events and mortality.

AIMS/HYPOTHESIS: Low birthweight is a risk factor for type 2 diabetes and CVD. This prospective cohort study investigated whether lower birthweight increases CVD risk after diagnosis of type 2 diabetes. METHODS: Original midwife records were evaluated for 8417 participants recently diagnosed with type 2 diabetes in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort. Patients were followed for the first occurrence of a composite CVD endpoint (myocardial infarction, coronary revascularisation, peripheral arterial disease, stroke, unstable angina, heart failure or CVD death), a three-component endpoint comprising major adverse cardiovascular events (MACE), and all-cause mortality. Ten-year risks were estimated using the Aalen-Johansen estimator considering non-CVD death as a competing risk. HRs were determined by Cox regression. Models were controlled for sex, age, calendar year at birth, family history of diabetes and born-at-term status. RESULTS: A total of 1187 composite CVD endpoints, 931 MACE, and 1094 deaths occurred during a median follow-up period of 8.5 years. The 10-year standardised composite CVD risk was 19.8% in participants with a birthweight <3000 g compared with 16.9% in participants with a birthweight of 3000-3700 g, yielding a risk difference (RD) of 2.9% (95% CI 0.4, 5.4) and an adjusted HR of 1.20 (95% CI 1.03, 1.40). The 10-year MACE risk for birthweight <3000 g was similarly elevated (RD 2.4%; 95% CI 0.1, 4.7; HR 1.22; 95% CI 1.01, 1.46). The elevated CVD risk was primarily driven by stroke, peripheral arterial disease and CVD death. All-cause mortality showed no substantial difference. CONCLUSIONS/INTERPRETATION: Having a birthweight <3000 g is associated with higher CVD risk among patients with type 2 diabetes, driven primarily by risk of stroke and CVD death.

Risk factor analysis for a rapid progression of chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a growing global health concern. Identifying individuals in routine clinical care with new-onset CKD at high risk of rapid progression of the disease is imperative to guide allocation of prophylactic interventions, but community-based data are limited. We aimed to examine the risk of rapid progression, kidney failure, hospitalization and death among adults with incident CKD stage G3 and to clarify the association between predefined risk markers and rapid CKD progression. METHODS: Using plasma creatinine measurements for the entire Danish population from both hospitals and primary care, we conducted a nationwide, population-based cohort study, including adults in Denmark with incident CKD stage G3 in 2017-2020. We estimated 3-year risks of rapid progression (defined by a confirmed decline in estimated glomerular filtration rate of ≥5 mL/min/1.73 m2/year), kidney failure, all-cause hospitalization and death. To examine risk markers, we constructed a heat map showing the risk of rapid progression based on predefined markers: albuminuria, sex, diabetes and hypertension/cardiovascular disease. RESULTS: Among 133 443 individuals with incident CKD stage G3, the 3-year risk of rapid progression was 14.6% [95% confidence interval (CI) 14.4-14.8]. The 3-year risks of kidney failure, hospitalization and death were 0.3% (95% CI 0.3-0.4), 53.3% (95% CI 53.0-53.6) and 18.1% (95% CI 17.9-18.4), respectively. In the heat map, the 3-year risk of rapid progression ranged from 7% in females without albuminuria, hypertension/cardiovascular disease or diabetes, to 46%-47% in males and females with severe albuminuria, diabetes and hypertension/cardiovascular disease. CONCLUSION: This population-based study shows that CKD stage G3 is associated with considerable morbidity in a community-based setting and underscores the need for optimized prophylactic interventions among such patients. Moreover, our data highlight the potential of using easily accessible markers in routine clinical care to identify individuals who are at high risk of rapid progression.

Liver, renal, genitourinary and diabetic ketoacidosis risks among new users of empagliflozin versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: Post-authorization safety study based on multinational cohorts.

AIM: To estimate risks of diabetic ketoacidosis (DKA), acute liver injury (ALI), acute kidney injury (AKI), chronic kidney disease (CKD), severe complications of urinary tract infection (UTI) and genital infection (GI) among patients with type 2 diabetes initiating empagliflozin versus those initiating a dipeptidyl peptidase-4 (DPP-4) inhibitor. MATERIALS AND METHODS: In this large multinational, observational, new-user cohort study in UK, Danish and US healthcare data sources, patients initiated empagliflozin or a DPP-4 inhibitor between August 2014 and August 2019, were aged ≥18 years, and had ≥12 months' continuous health plan enrolment. Incidence rates by exposure and incidence rate ratios, adjusted for propensity-score deciles, were calculated. RESULTS: In total, 64 599 empagliflozin initiators and 203 315 DPP-4 inhibitor initiators were included. There was an increased risk [pooled adjusted incidence rate ratios (95% confidence interval)] of DKA [2.19 (1.74-2.76)] and decreased risks of ALI [0.77 (0.50-1.19) in patients without predisposing conditions of liver disease; 0.70 (0.56-0.88) in all patients] and AKI [0.54 (0.41-0.73)]. In the UK data, there was an increased risk of GI [males: 4.04 (3.46-4.71); females: 3.24 (2.81-3.74)] and decreased risks of CKD [0.53 (0.43-0.65)] and severe complications of UTI [0.51 (0.37-0.72)]. The results were generally consistent in subgroup and sensitivity analyses. CONCLUSIONS: Compared with DDP-4 inhibitor use, empagliflozin use was associated with increased risks of DKA and GI and decreased risks of ALI, AKI, CKD and severe complications of UTI. These associations are consistent with previous studies and known class effects of sodium-glucose cotransporter 2 inhibitors, including renoprotective effects and beneficial effects on alanine aminotransferase levels.

Lifetime and 10-year cardiovascular risk prediction in individuals with type 1 diabetes: The LIFE-T1D model.

AIMS: To develop and externally validate the LIFE-T1D model for the estimation of lifetime and 10-year risk of cardiovascular disease (CVD) in individuals with type 1 diabetes. MATERIALS AND METHODS: A sex-specific competing risk-adjusted Cox proportional hazards model was derived in individuals with type 1 diabetes without prior CVD from the Swedish National Diabetes Register (NDR), using age as the time axis. Predictors included age at diabetes onset, smoking status, body mass index, systolic blood pressure, glycated haemoglobin level, estimated glomerular filtration rate, non-high-density lipoprotein cholesterol, albuminuria and retinopathy. The model was externally validated in the Danish Funen Diabetes Database (FDDB) and the UK Biobank. RESULTS: During a median follow-up of 11.8 years (interquartile interval 6.1-17.1 years), 4608 CVD events and 1316 non-CVD deaths were observed in the NDR (n = 39 756). The internal validation c-statistic was 0.85 (95% confidence interval [CI] 0.84-0.85) and the external validation c-statistics were 0.77 (95% CI 0.74-0.81) for the FDDB (n = 2709) and 0.73 (95% CI 0.70-0.77) for the UK Biobank (n = 1022). Predicted risks were consistent with the observed incidence in the derivation and both validation cohorts. CONCLUSIONS: The LIFE-T1D model can estimate lifetime risk of CVD and CVD-free life expectancy in individuals with type 1 diabetes without previous CVD. This model can facilitate individualized CVD prevention among individuals with type 1 diabetes. Validation in additional cohorts will improve future clinical implementation.

Low-grade inflammation in persons with recently diagnosed type 2 diabetes: The role of abdominal adiposity and putative mediators.

AIMS: To determine the magnitude of the association between abdominal adiposity and low-grade inflammation in persons with recently diagnosed type 2 diabetes (T2D) and to determine to what extent this association is mediated by low physical activity level, hyperinsulinaemia, hyperglycaemia, dyslipidaemia, hypertension, and comorbidities. MATERIALS AND METHODS: We measured waist circumference, clinical characteristics, and inflammatory markers i.e. tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP), in >9000 persons with recently diagnosed T2D. We applied multiple mediation analysis using structural equation modelling, with adjustment for age and sex. RESULTS: Waist circumference as a proxy for abdominal adiposity was positively associated with all inflammatory markers. Hence, a one-standard deviation (SD) increase in waist circumference (SD = 15 cm) was associated with a 22%, 35%, and 46% SD increase in TNF-α (SD = 1.5 pg/mL), IL-6 (SD = 4.4 pg/mL), and hsCRP (SD = 6.9 mg/L), respectively. The level of hyperinsulinaemia assessed by fasting C-peptide was quantitatively the most important mediator, accounting for 9%-25% of the association between abdominal adiposity and low-grade inflammation, followed by low physical activity (5%-7%) and high triglyceride levels (2%-6%). Although mediation of adiposity-induced inflammation by greater comorbidity and higher glycated haemoglobin levels reached statistical significance, their impact was minor (1%-2%). CONCLUSIONS: In persons with recently diagnosed T2D, there was a clear association between abdominal adiposity and low-grade inflammation. A considerable part (20%-40%) of this association was mediated by other factors, with hyperinsulinaemia as a potentially important driver of adiposity-induced inflammation in T2D.

Birthweight is associated with clinical characteristics in people with recently diagnosed type 2 diabetes.

AIMS/HYPOTHESIS: Low birthweight is a risk factor for type 2 diabetes but it is unknown whether low birthweight is associated with distinct clinical characteristics at disease onset. We examined whether a lower or higher birthweight in type 2 diabetes is associated with clinically relevant characteristics at disease onset. METHODS: Midwife records were traced for 6866 individuals with type 2 diabetes in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort. Using a cross-sectional design, we assessed age at diagnosis, anthropomorphic measures, comorbidities, medications, metabolic variables and family history of type 2 diabetes in individuals with the lowest 25% of birthweight (<3000 g) and highest 25% of birthweight (>3700 g), compared with a birthweight of 3000-3700 g as reference, using log-binomial and Poisson regression. Continuous relationships across the entire birthweight spectrum were assessed with linear and restricted cubic spline regression. Weighted polygenic scores (PS) for type 2 diabetes and birthweight were calculated to assess the impact of genetic predispositions. RESULTS: Each 1000 g decrease in birthweight was associated with a 3.3 year (95% CI 2.9, 3.8) younger age of diabetes onset, 1.5 kg/m2 (95% CI 1.2, 1.7) lower BMI and 3.9 cm (95% CI 3.3, 4.5) smaller waist circumference. Compared with the reference birthweight, a birthweight of <3000 g was associated with more overall comorbidity (prevalence ratio [PR] for Charlson Comorbidity Index Score ≥3 was 1.36 [95% CI 1.07, 1.73]), having a systolic BP ≥155 mmHg (PR 1.26 [95% CI 0.99, 1.59]), lower prevalence of diabetes-associated neurological disease, less likelihood of family history of type 2 diabetes, use of three or more glucose-lowering drugs (PR 1.33 [95% CI 1.06, 1.65]) and use of three or more antihypertensive drugs (PR 1.09 [95% CI 0.99, 1.20]). Clinically defined low birthweight (<2500 g) yielded stronger associations. Most associations between birthweight and clinical characteristics appeared linear, and a higher birthweight was associated with characteristics mirroring lower birthweight in opposite directions. Results were robust to adjustments for PS representing weighted genetic predisposition for type 2 diabetes and birthweight. CONCLUSION/INTERPRETATION: Despite younger age at diagnosis, and fewer individuals with obesity and family history of type 2 diabetes, a birthweight <3000 g was associated with more comorbidities, including a higher systolic BP, as well as with greater use of glucose-lowering and antihypertensive medications, in individuals with recently diagnosed type 2 diabetes.

Burden of Chronic Obstructive Pulmonary Disease Attributable to Tuberculosis: A Microsimulation Study.

Tuberculosis (TB) is a risk factor for chronic obstructive pulmonary disease (COPD), but COPD is also a predictor of TB. The excess life-years lost to COPD caused by TB can potentially be saved by screening for and treating TB infection. We examined the number of life-years that could be saved by preventing TB and TB-attributable COPD. We compared the observed (no intervention) and counterfactual microsimulation models constructed from observed rates in the Danish National Patient Registry (covering all Danish hospitals between 1995 and 2014). In the Danish population of TB and COPD-naive individuals (n = 5,206,922), 27,783 persons (0.5%) developed TB. Among those who developed TB, 14,438 (52.0%) developed TB with COPD. Preventing TB saved 186,469 life-years overall. The excess number of life-years lost to TB alone was 7.07 years per person, and the additional number of life-years lost among persons who developed COPD after TB was 4.86 years per person. The life-years lost to TB-associated COPD are substantial, even in regions where TB can be expected to be identified and treated promptly. Prevention of TB could prevent a substantial amount of COPD-related morbidity; the benefit of screening and treatment for TB infection is underestimated by considering morbidity from TB alone.

Breast cancer and incidence of type 2 diabetes mellitus: a systematic review and meta-analysis.

PURPOSE: Breast cancer and its treatments may increase the risk of type 2 diabetes (T2D). We conducted a systematic review and meta-analysis to investigate the association between breast cancer and the incidence of T2D overall, and according to breast cancer treatments. METHODS: We searched PubMed, Embase and references of relevant papers for studies on breast cancer, breast cancer treatment, and subsequent T2D risk. Using random-effects models, we calculated effect estimates and associated 95% confidence intervals of the association between breast cancer, adjuvant breast cancer treatments (i.e., endocrine therapy (tamoxifen, aromatase inhibitors, and combined) and chemotherapy), and subsequent T2D. We used funnel plots to assess publication bias. RESULTS: Among 15 eligible studies, 10 reported on T2D risk after breast cancer, chemotherapy, or endocrine therapy; five studies investigated more than one association. Compared with patients without breast cancer, those with breast cancer and those who received any endocrine therapy had elevated risk of incident T2D (EE = 1.23, 95% CI = 1.13-1.33 and EE = 1.23, 95% CI = 1.16-1.32, respectively). Among breast cancer patients only, the risk of T2D was higher for those who received tamoxifen compared with those who did not receive tamoxifen (EE = 1.28, 95% CI = 1.18-1.38). Due to few studies, analyses investigating T2D risk after treatment with aromatase inhibitors or chemotherapy were inconclusive. CONCLUSION: Our findings suggest an elevated risk of T2D in breast cancer survivors, particularly after tamoxifen therapy. Further research is needed to determine the impact of aromatase inhibitors, and chemotherapy on the incidence of T2D after breast cancer.

Changes in the use of glucose-lowering drugs: A Danish nationwide study.

AIM: To investigate changes in the pattern of drugs used to treat type 2 diabetes in Denmark from 2005 to 2021. MATERIALS AND METHODS: A nationwide, population-based drug utilization study based on medical databases covering the Danish population was conducted. We assessed incident and prevalent use patterns among all 441 205 individuals initiating at least one non-insulin, glucose-lowering drug. RESULTS: The rate of new users of non-insulin, glucose-lowering drugs increased from 2005, peaked in 2011, decreased to stable levels during 2013 to 2019, then increased dramatically during 2020-2021. The prevalence of use increased from 2.1% (in 2005) to 5.0% (in 2021) of the entire adult population. In 2021, metformin comprised 39% of all glucose-lowering drug consumption, followed by insulin (17%), sodium-glucose co-transporter-2 inhibitors (SGLT-2is) (17%), glucagon-like peptide-1 receptor agonists (GLP-1RAs) (16%) and dipeptidyl peptidase-4 inhibitors (7.5%). Overall, 56% of users were on monotherapy, 28% used dual therapy, while 13% and 2.8% used three and four drug classes, respectively. Both the intensity and diversity of therapies increased substantially over time, with 15 different treatment regimens each covering more than 1% of users in 2021. General practitioners prescribed 88% of all glucose-lowering drugs. Marked shifts towards GLP-1RA initiation by general practitioners and SGLT-2i initiation by specialists were observed, and changing user profiles suggested increasing use for non-diabetes indications. CONCLUSIONS: The rate of new users of non-insulin, glucose-lowering drugs has increased in recent years and the prevalence of glucose-lowering drug use increases steadily. Glucose-lowering drugs are mainly prescribed by general practitioners, and the intensity, diversity and indications of glucose-lowering treatment are increasing.

Hospital-diagnosed morbidities and recent surgery as risk factors for developing Guillain-Barré syndrome.

BACKGROUND AND PURPOSE: This study was undertaken to determine the association of hospital-diagnosed morbidity and recent surgery with risk of subsequent Guillain-Barré syndrome (GBS) development. METHODS: We conducted a nationwide population-based case-control study of all patients with first-time hospital-diagnosed GBS in Denmark between 2004 and 2016 and 10 age-, sex-, and index date-matched population controls per case. Hospital-diagnosed morbidities included in the Charlson Comorbidity Index were assessed as GBS risk factors up to 10 years prior to the GBS index date. Incident major surgery was assessed within 5 months prior. RESULTS: In the 13-year study period, there were 1086 incident GBS cases, whom we compared with 10,747 matched controls. Any pre-existing hospital-diagnosed morbidity was observed in 27.5% of GBS cases and 20.0% of matched controls, yielding an overall matched odds ratio (OR) of 1.6 (95% confidence interval [CI] = 1.4-1.9). The strongest associations were found for leukemia, lymphoma, diabetes, liver disease, myocardial infarction, congestive heart failure, and cerebrovascular disease, with 1.6- to 4.6-fold increased risks of subsequent GBS. GBS risk was strongest for morbidities newly diagnosed during the past 5 months (OR = 4.1, 95% CI = 3.0-5.6). Surgical procedures within 5 months prior were observed in 10.6% of cases and 5.1% of controls, resulting in a GBS OR of 2.2 (95% CI = 1.8-2.7). Risk of developing GBS was highest during the first month following surgery (OR = 3.7, 95% CI = 2.6-5.2). CONCLUSIONS: In this large nationwide study, individuals with hospital-diagnosed morbidity and recent surgery had a considerably increased risk of GBS.

A Within-Subject Before-After Study of the Impact of Antidepressants on Hemoglobin A1c and Low-Density Lipoprotein Levels in Type 2 Diabetes.

PURPOSE/BACKGROUND: Data on the effect of treatment with antidepressant drugs on metabolic control in diabetes are sparse. In this controlled within-subject before-after study, the impact of initiation and discontinuation of antidepressant treatment on hemoglobin A1c (HbA1c) and low-density lipoprotein (LDL) levels in type 2 diabetes was estimated. METHODS/PROCEDURES: All individuals with newly developed type 2 diabetes (first HbA1c ≥ 6.5%) between 2000 and 2016 in Northern and Central Denmark were identified using register-based health care data. Among these, we identified individuals initiating and discontinuing antidepressant treatment. Using a within-subject before-after design, we examined HbA1c and LDL in the 16 months leading up to and the 16 months after antidepressant treatment initiation or discontinuation, respectively. For comparison, we ran similar time trend analyses in a reference population of age- and sex-matched type 2 diabetes individuals not receiving antidepressant treatment. FINDINGS/RESULTS: Mean HbA1c decreased after initiation of antidepressant treatment (-0.16%; 95% confidence interval [CI], -0.18 to -0.13%). In the reference population, no material change in HbA1c over time (-0.03%; 95% CI, -0.04 to -0.01%) was seen. Mean LDL decreased not only in antidepressant initiators (-0.17 mmol/L; 95% CI, -0.19 to -0.15 mmol/L) but also in the reference population (-0.15 mmol/L; 95% CI, -0.16 to -0.13 mmol/L). Among antidepressant discontinuers, there was also a decrease in HbA1c (-0.32%; 95% CI, -0.37 to -0.28%), with no change in the reference population (-0.02%; 95% CI, -0.04 to 0.00%). Decreases in LDL were found both in antidepressant discontinuers (-0.09 mmol/L; 95% CI, -0.14 to -0.04 mmol/L) and in the reference population (-0.16 mmol/L0; 95% CI, -0.18 to -0.13 mmol/L). IMPLICATIONS/CONCLUSIONS: Antidepressant treatment in type 2 diabetes may have a beneficial effect on glycemic control, as the decrease in HbA1c after discontinuation of antidepressants likely reflects remission of depression. Conversely, antidepressant treatment does not seem to affect LDL levels.

The impact of hospital-diagnosed depression or use of antidepressants on treatment initiation, adherence and HbA1c/LDL target achievement in newly diagnosed type 2 diabetes.

AIMS/HYPOTHESIS: We aimed to assess whether current antidepressant therapy or a history of hospital-diagnosed depression affects diabetes treatment initiation, adherence, and HbA1c and LDL-cholesterol target achievement. METHODS: In this register-based study, we included all individuals from Central and Northern Denmark with newly diagnosed type 2 diabetes, defined as a first-ever HbA1c measurement of ≥48 mmol/mol (6.5%), between 2000 and 2016. Individuals either diagnosed with depression at a psychiatric hospital in the 2 years prior to their diabetes diagnosis or currently receiving treatment with an antidepressant were compared with individuals with type 2 diabetes, but without depression treatment or previous history of depression. Outcome measures included initiation of glucose-lowering drugs and lipid-modifying agents, adherence to these medications (medication possession ratio >80%), and HbA1c (<53 mmol/mol [7%]) and LDL-cholesterol (<2.6 mmol/l) target achievement. The assessment of association between depression or antidepressant treatment and these outcomes was conducted using regression analyses with adjustment for potential confounders. RESULTS: We included a total of 87,650 individuals with first-ever HbA1c-diagnosed type 2 diabetes, of whom 0.9% (n = 784) had hospital-diagnosed depression and 11.4% (n = 9963) currently received antidepressant treatment. Compared with those without depression treatment, treatment with an antidepressant was associated with increased likelihood of glucose-lowering drug initiation (HR 1.39 [95% CI 1.34, 1.44]) and adherence (OR 1.27 [95% CI 1.18, 1.36]), lipid-modifying agent initiation (HR 1.17 [95% CI 1.11, 1.23]) and adherence (OR 1.25 [95% CI 1.09, 1.43]), and achievement of LDL (OR 1.08 [95% CI 1.03, 1.14]) but not HbA1c target (OR 0.99 [95% CI 0.93, 1.06]). The findings were similar for individuals who had hospital-diagnosed depression. CONCLUSIONS/INTERPRETATION: In individuals with newly diagnosed type 2 diabetes, antidepressant treatment and depression were associated with improved diabetes treatment quality. Graphical abstract.

Real-world use of cardioprotective glucose-lowering drugs in patients with type 2 diabetes and cardiovascular disease: A Danish nationwide cohort study, 2012 to 2019.

AIMS: To investigate temporal trends in time to initiation of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide 1 analogues (cardioprotective glucose-lowering drugs [GLDs]) in patients with a new dual diagnosis of type 2 diabetes (T2DM) and cardiovascular disease (CVD). MATERIALS AND METHODS: In a cohort study, we identified patients with a new dual diagnosis of T2DM and CVD using linked healthcare data from nationwide registries on drug prescriptions and diagnosis codes. For each calendar year between 2012 and 2018, we examined time to initiation and cumulative user proportions (CUPs) for cardioprotective GLD use 1 and 2 years after the dual diagnosis. RESULTS: Among all individuals living in Denmark in the period 2012 to 2018, 41 733 patients with a new dual diagnosis of T2DM and CVD were identified (median [interquartile range] age 71 [64-79] years, 61% male, and 57% with CVD as the latest diagnosis). Incidence curve slopes and 1- and 2-year CUPs for cardioprotective GLDs increased during the study period (1-year CUP 4.0%, 95% confidence interval [CI] 3.6-4.5) in 2012 to 14.7, 95% CI 13.7-15.7, in 2018; 2-year CUP 5.5, 95% CI 5.0-6.1, in 2012 to 16.7, 95% CI 15.8-17.7, in 2017). T2DM patients with CVD as the second (latest) diagnosis had higher 1-year CUPs than CVD patients with T2DM as the latest diagnosis: 2012: 7.0 (95% CI 6.2-8.0) versus 1.4 (95% CI 1.0-1.8); 2018: 18.1 (95% CI 16.8-19.6) versus 10.0 (95% CI 8.8-11.3). CONCLUSIONS: In patients with T2DM and CVD, the incidence of cardioprotective GLD initiation increased between 2012 and 2018, however, within 2 years of dual diagnosis, it remained low.

Incident psychopharmacological treatment and psychiatric hospital contact in individuals with newly developed type 2 diabetes - a register-based cohort study.

To investigate the association between newly developed type 2 diabetes (T2D) and incident psychopharmacological treatment and psychiatric hospital contact. Via Danish registers, we identified all 56 640 individuals from the Central and Northern Denmark Regions with newly developed T2D (defined by the first HbA1c measurement ≥6.5%) in 2000-2016 as well as 315 694 age- and sex-matched controls (without T2D). Those having received psychopharmacological treatment or having had a psychiatric hospital contact in the 5 years prior to the onset of T2D were not included. For this cohort, we first assessed the 2-year incidence of psychopharmacological treatment and psychiatric hospital contact. Secondly, via Cox regression, we compared the incidence of psychopharmacological treatment/psychiatric hospital contact among individuals with T2D to propensity score-matched controls - taking a wide range of potential confounders into account. Finally, via Cox proportional hazards regression, we assessed which baseline (T2D onset) characteristics were associated with subsequent psychopharmacological treatment and psychiatric hospital contact. A total of 8.3% of the individuals with T2D initiated psychopharmacological treatment compared to 4.6% of the age- and sex-matched controls. Individuals with T2D were at increased risk of initiating psychopharmacological treatment compared to the propensity score-matched controls (HR = 1.51, 95% CI = 1.43-1.59), whereas their risk of psychiatric hospital contact was not increased to the same extent (HR = 1.14, 95% CI = 0.98-1.32). Older age, somatic comorbidity, and being divorced/widowed were associated with both psychopharmacological treatment and psychiatric hospital contact following T2D. Individuals with T2D are at elevated risk of requiring psychopharmacological treatment.

Effect of Roux-en-Y gastric bypass surgery on diabetes remission and complications in individuals with type 2 diabetes: a Danish population-based matched cohort study.

AIMS/HYPOTHESIS: The aim of this study was to examine the effect of Roux-en-Y gastric bypass (RYGB) surgery on diabetes remission, subsequent diabetes relapse and micro- and macrovascular complications in individuals with type 2 diabetes and obesity (BMI >35 kg/m2) in a real-world setting. METHODS: This was a population-based cohort study of 1111 individuals with type 2 diabetes treated by RYGB at hospitals in Northern Denmark (2006-2015), and 1074 matched non-operated individuals with type 2 diabetes. Diabetes remission was defined as no glucose-lowering drug use with HbA1c <48 mmol/mol (<6.5%), or metformin monotherapy with HbA1c <42 mmol/mol (<6.0%). Data on complications were ascertained from medical registries with complete follow-up. RESULTS: At 1 year of follow-up, 74% of the cohort treated by RYGB experienced diabetes remission, while 27% had relapsed after 5 years. Predictors of non-remission were age >50 years, diabetes duration >5 years, use of glucose-lowering drugs other than metformin, and baseline HbA1c >53 mmol/mol (>7.0%). Compared with the non-operated cohort using adjusted Cox regression (5.3 years follow-up), the cohort treated by RYGB had 47% lower risk of microvascular complications (HR 0.53 [95% CI 0.38, 0.73]) and a statistically non-significant 24% lower risk of macrovascular complications (HR 0.76 [95% CI 0.49, 1.18]). Diabetes remission vs non-remission at 1 year was associated with reduced HR of 0.43 (95% CI 0.25, 0.72) for microvascular complications and with HR of 0.76 (95% CI 0.40, 1.45) for macrovascular complications. CONCLUSIONS/INTERPRETATION: In routine clinical care, three out of four individuals with type 2 diabetes and obesity treated by RYGB experienced diabetes remission after 1 year, whereas 27% of these individuals had relapsed at 5 years follow-up. RYGB was associated with substantially decreased risk of microvascular complications and non-significantly fewer macrovascular complications, with early diabetes remission as a clear predictor of reduced microvascular complications.

Pathophysiology-based phenotyping in type 2 diabetes: A clinical classification tool.

BACKGROUND: Type 2 diabetes may be a more heterogeneous disease than previously thought. Better understanding of pathophysiological subphenotypes could lead to more individualized diabetes treatment. We examined the characteristics of different phenotypes among 5813 Danish patients with new clinically diagnosed type 2 diabetes. METHODS: We first identified all patients with rare subtypes of diabetes, latent autoimmune diabetes of adults (LADA), secondary diabetes, or glucocorticoid-associated diabetes. We then used the homeostatic assessment model to subphenotype all remaining patients into insulinopenic (high insulin sensitivity and low beta cell function), classical (low insulin sensitivity and low beta cell function), or hyperinsulinemic (low insulin sensitivity and high beta cell function) type 2 diabetes. RESULTS: Among 5813 patients diagnosed with incident type 2 diabetes in the community clinical setting, 0.4% had rare subtypes of diabetes, 2.8% had LADA, 0.7% had secondary diabetes, 2.4% had glucocorticoid-associated diabetes, and 93.7% had WHO-defined type 2 diabetes. In the latter group, 9.7% had insulinopenic, 63.1% had classical, and 27.2% had hyperinsulinemic type 2 diabetes. Classical patients were obese (median waist 105 cm), and 20.5% had cardiovascular disease (CVD) at diagnosis, while insulinopenic patients were fairly lean (waist 92 cm) and 17.5% had CVD (P = 0.14 vs classical diabetes). Hyperinsulinemic patients were severely obese (waist 112 cm), and 25.5% had CVD (P < 0.0001 vs classical diabetes). CONCLUSIONS: Patients clinically diagnosed with type 2 diabetes are a heterogeneous group. In the future, targeted treatment based on pathophysiological characteristics rather than the current "one size fits all" approach may improve patient prognosis.

Elevated potassium levels in patients with chronic kidney disease: occurrence, risk factors and clinical outcomes-a Danish population-based cohort study.

Background: Data on the true burden of hyperkalemia (HK) in patients with chronic kidney disease (CKD) in a real-world setting are scarce. Methods: The incidence rate of HK [first blood test with an elevated blood potassium level level >5.0 mmol/L] in primary or hospital care was assessed in a population-based cohort of all newly diagnosed CKD patients [second estimated glomerular filtration rate (eGFR) measurement <60 mL/min/1.73 m2 or hospital diagnosis] in northern Denmark. Risk factors and clinical outcomes were compared for CKD patients with HK and matched CKD patients without HK. Results: Of 157 766 patients with CKD, 28% experienced HK, for an overall HK incidence rate of 70/1000 person-years. Among patients with Stage 3A, 3B, 4 or 5 CKD, 9, 18, 31 and 42%, respectively, experienced HK within the first year. Important HK risk factors included diabetes {prevalence ratio [PR] 1.74 [95% confidence interval (CI) 1.69-1.79]}, heart failure [PR 2.31 (95% CI 2.23-2.40)] and use of angiotensin-converting enzyme inhibitors [PR 1.45 (95% CI 1.42-1.48)], potassium supplements [PR 1.59 (95% CI 1.55-1.62)] or spironolactone [PR 2.53 (95% CI 2.44-2.63)]. In CKD patients who developed HK, 34% had any acute hospitalization 6 months before the HK event, increasing to 57% 6 months after HK [before-after risk ratio 1.72 (95% CI 1.69-1.74)]. The 6-month mortality following HK was 26%, versus 6% in matched non-HK patients. Compared with non-HK patients, 6-month hazard ratios for any acute hospitalization in HK patients were 2.11-fold higher, including hazard ratios of 2.07 for cardiac diagnoses, 2.29 for ventricular arrhythmias, 3.26 for cardiac arrest, 4.77 for intensive care and 4.85 for death. Conclusions: More than one in four CKD patients develops HK. Patients with severe CKD, diabetes, heart failure or use of spironolactone are at high risk. HK is associated with severe clinical outcomes.

In utero beta-2-adrenergic agonists exposure and risk of epilepsy: A Danish nationwide population-based cohort study.

PURPOSE: To examine the association between maternal use of beta-2-adrenergic agonists (ß2AAs) and the risk of epilepsy in offspring. METHODS: A nationwide retrospective cohort study was performed based on Danish registries. Children of mothers who used ß2AAs during pregnancy were allocated to the exposed group and other children to the unexposed group. The outcome was a diagnosis of epilepsy. Cox regression was performed to estimate the hazard ratios (HRs) of epilepsy after adjusting for parental and children factors. To evaluate confounding by indication, we extended the exposure time window from 2 years before pregnancy and stratified the analyses by maternal asthma, in particular analyses by trimesters. RESULTS: The exposed children had a 1.24-fold risk of epilepsy (HR = 1.24, 95% confidence interval [CI]: 1.12, 1.38). Compared with no prenatal exposure from 2 years before pregnancy through delivery, the HR was 1.11 (95% CI: 1.01, 1.22) in children of mothers with ß2AAs use only before pregnancy, 1.28 (95% CI: 1.09, 1.50) only during pregnancy, and 1.23 (95% CI: 1.07, 1.41) both before and during pregnancy. The increased risk was only observed in children of mothers with ß2AAs use in the first (HR = 1.33, 95% CI: 1.01, 1.75) or second trimesters (HR = 1.35, 95% CI: 1.05, 1.74), but not the third trimester. CONCLUSIONS: In utero exposure to ß2AAs, particularly in the first or second trimesters, may be associated with an increased risk of epilepsy. It may partly be due to the indication of ß2AAs use, but a direct effect of ß2AAs cannot be ruled out.

Lifestyle Factors and Early Clinical Outcome in Patients With Acute Stroke: A Population-Based Study.

BACKGROUND AND PURPOSE: We examined the associations of individual and combined lifestyle factors with early adverse stroke outcomes. METHODS: A total of 82 597 patients were identified from nationwide registries. Lifestyle factors at the time of stroke admission included body mass index (kg/m2), smoking habits, and alcohol intake, which were grouped (healthy, moderately healthy, moderately unhealthy, and unhealthy). The associations between lifestyle and outcomes were examined using multivariable regression. RESULTS: A total of 18.3% had a severe stroke, 7.8% pneumonia, 12.5% urinary tract infection, and 9.9% died within 30 days. The association between lifestyle, stroke severity, and mortality, respectively, differed according to sex. Unhealthy lifestyle was associated with lower risk of severe stroke (adjusted odds ratio [OR], 0.73; 95% confidence interval [CI], 0.63-0.84) and 30-day mortality among men (adjusted OR, 0.71; 95% CI, 0.58-0.87), but not among women (severe stroke: adjusted OR, 1.14; 95% CI, 0.85-1.55, and mortality: adjusted OR, 1.34; 95% CI, 0.90-1.99). No sex differences were found for pneumonia and urinary tract infection. Unhealthy lifestyle was not associated with a statistically significant increased risk of developing in-hospital pneumonia (adjusted OR, 1.30; 95% CI, 0.98-1.73) or urinary tract infection (adjusted OR, 0.98; 95% CI, 0.72-1.33). Underweight was associated with a higher 30-day mortality (men: adjusted OR, 1.71; 95% CI, 1.50-1.96, and women: adjusted OR, 1.46; 95% CI, 1.34-1.60). CONCLUSIONS: Healthy lifestyle was not associated with a lower risk of adverse stroke outcomes, in particularly among men. However, underweight may be a particular concern being associated with an increased risk of adverse outcomes among both sexes.

Impact of Glycemic Control on Risk of Infections in Patients With Type 2 Diabetes: A Population-Based Cohort Study.

Infections are a major clinical challenge for type 2 diabetes patients, but little is known about the impact of glycemic control. We used Cox regression analyses to examine the association between baseline and time-varying hemoglobin A1c (HbA1c) values and development of community antiinfective-agent-treated and hospital-treated infections in 69,318 patients with type 2 diabetes diagnosed between 2000 and 2012 in Northern Denmark. Incidence rates were 394/1,000 patient-years for community-treated infections and 63/1,000 patient-years for hospital-treated infections. The adjusted hazard ratios for community-treated infection at an HbA1c level of ≥10.50%, as compared with 5.50%-<6.49%, were 0.97 (95% confidence interval (CI): 0.94, 1.00) for HbA1c measured at early baseline, 1.09 (95% CI: 1.03, 1.14) for updated mean HbA1c, 1.13 (95% CI: 1.08, 1.19) for updated time-weighted mean HbA1c, and 1.19 (95% CI: 1.14, 1.26) for the latest updated HbA1c. Corresponding estimates for hospital-treated infections were 1.08 (95% CI: 1.02, 1.14) for early baseline HbA1c, 1.55 (95% CI: 1.42, 1.71) for updated mean HbA1c, 1.58 (95% CI: 1.44, 1.72) for updated time-weighted mean HbA1c, and 1.64 (95% CI: 1.51, 1.79) for the latest updated HbA1c. Our findings provide evidence for an association between current hyperglycemia and infection risk in type 2 diabetes patients.