Acute urinary retention in men: 21-year trends in incidence, subsequent benign prostatic hyperplasia-related treatment and mortality: A Danish population-based cohort study.

OBJECTIVE: To examine trends in incidence of acute urinary retention, subsequent benign prostatic hyperplasia-related treatment and mortality in the era of medical therapy for benign prostatic hyperplasia. Additionally, to compare mortality with the general population. MATERIALS AND METHODS: We conducted a Danish nationwide registry-based study including 70,775 men aged 45 years or older with a first hospitalization for acute urinary retention during 1997-2017. We computed annual standardized incidence rates, subsequent 1-year cumulative incidence of benign prostatic hyperplasia-related surgical and medical treatment, and standardized 3-month and 1-year mortality rates. Finally, we compared standardized all-cause and cause-specific mortality ratios with the general population. RESULTS: The standardized incidence rate of acute urinary retention per 1000 person-years increased transiently from 2.34 to 3.42 during 1997-2004, but gradually declined to 2.95 in 2017. The 1-year cumulative incidence of benign prostatic hyperplasia-related surgery declined from 31.2% to 19.8% and 20.5% to 7.7% after spontaneous and precipitated acute urinary retention, respectively. During 1997-2017, the standardized 1-year mortality declined from 22.2% to 17.2%. Compared with the general population, mortality was 4-5 times higher after 3 months and 2-3 times higher after 1 year of acute urinary retention. The cause-specific standardized mortality ratios were particularly high for deaths attributable to malignancies, urogenital disease, certain infections, chronic pulmonary disease, and diabetes. CONCLUSION: During 1997-2017, we observed a transient increase in the incidence of acute urinary retention. The subsequent use of benign prostatic hyperplasia-related surgery declined considerably and mortality continued to be high, mainly because of deaths from malignancies, urogenital disease, infections, and preexisting comorbidity.

Development and validation of a model for predicting mortality in patients with hip fracture.

OBJECTIVE: to develop a user-friendly prediction tool of 1-year mortality for patients with hip fracture, in order to guide clinicians and patients on appropriate targeted preventive measures. DESIGN: population-based cohort study from 2011 to 2017 using nationwide data from the Danish Hip Fracture Registry. SUBJECTS: a total of 28,791 patients age 65 and above undergoing surgery for a first-time hip fracture. METHODS: patient-related prognostic factors at the time of admission were assessed as potential predictors: Nursing home residency, comorbidity (Charlson Comorbidity Index [CCI] Score), frailty (Hospital Frailty Risk Score), basic mobility (Cumulated Ambulation Score), atrial fibrillation, fracture type, body mass index (BMI), age and sex. Association with 1-year mortality examined by determining the cumulative incidence, applying univariable logistic regression and assessing discrimination (area under the receiver operating characteristics curve [AUROC]). The final model (logistic regression) was utilised on a development cohort (70% of patients). Discrimination and calibration were assessed on the validation cohort (remaining 30% of patients). RESULTS: all predictors showed an association with 1-year mortality, but discrimination was moderate. The final model included nursing home residency, CCI Score, Cumulated Ambulation Score, BMI and age. It had an acceptable discrimination (AUROC 0.74) and calibration, and predicted 1-year mortality risk spanning from 5 to 91% depending on the combination of predictors in the individual patient. CONCLUSIONS: using information obtainable at the time of admission, 1-year mortality among patients with hip fracture can be predicted. We present a user-friendly chart for daily clinical practice and provide new insight regarding the interplay between prognostic factors.

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.

Systemic lupus erythematosus during pregnancy is not associated with school performance in offspring - A Danish population-based study.

INTRODUCTION: Systemic lupus erythematosus (SLE) in pregnancy is considered a risk factor for a range of adverse outcomes in the offspring. Studies have indicated increased risk of neurodevelopmental disorders such as autism spectrum disorders, dyslexia and ADHD. However, the overall long-term cognitive development of children born to women with SLE has scarcely been examined. In this study, we compare test scores from the Danish National School Tests of children born to women SLE with children of the background population. METHODS: We included all singleton children born in Denmark between 1995 and 2008, who were listed in the Danish National School Test Register (n=738,862). Children born to women with SLE were identified through linkage of national healthcare registers. We assessed the children's performance in the national school tests between 2nd and 8th grade, in reading and mathematics. Information on the mothers' redeemed prescriptions in pregnancy was included in stratified analyses. Differences of mean test scores were derived from linear regressions and compared according to maternal SLE status, and predefined categories of medication exposures. RESULTS: In total, 312 (0.04%) children were born to mothers with SLE. There were no differences in performance in neither reading nor mathematics tests between those born to mothers with SLE and children born to mothers without SLE. When stratifying on medication exposures among children whose mothers had SLE, there was a non-significant tendency towards poorer results among those exposed to hydroxychloroquine and/or immunosuppressants (n=31), compared to those not exposed to these medications. A similar tendency was not observed among children whose mothers received hydroxychloroquine for non-SLE reasons (n=1,235). CONCLUSION: This study indicates no major harmful effect on the child's neurocognitive development from exposure in utero to SLE, hydroxychloroquine and/or immunosuppressants, as measured by school performance.

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.

A large remaining potential in lipid-lowering drug treatment in the type 2 diabetes population: A Danish nationwide cohort study.

AIM: To assess lipid-lowering drug (LLD) use patterns during 1996-2017 and examine lipid levels in relation to the use of LLDs and prevalent atherosclerotic cardiovascular disease (ASCVD). METHODS: Using a nationwide diabetes register, 404 389 individuals with type 2 diabetes living in Denmark during 1996-2017 were identified. Individuals were followed from 1 January 1996 or date of type 2 diabetes diagnosis until date of emigration, death or 1 January 2017. Redemptions of prescribed LLDs were ascertained from the nationwide Register of Medicinal Products Statistics. Data on lipid levels were sourced from the National Laboratory Database since 2010. LLD coverage was calculated at any given time based on the redeemed amount and dose. Trends in lipid levels were estimated using an additive mixed-effect model. Low-density lipoprotein cholesterol (LDL-C) goal attainment was assessed based on recommended targets by the 2011, 2016 and 2019 guidelines for management of dyslipidaemias. RESULTS: LLD use has decreased since 2012 and only 55% of those with type 2 diabetes were LLD users in 2017. A decline in levels of total cholesterol and LDL-C, and an increase in triglycerides, was observed during 2010-2017. Annual mean levels of LDL-C were lower among LLD users compared with non-users (in 2017: 1.84 vs. 2.57 mmol/L). A greater fraction of LLD users achieved the LDL-C goal of less than 1.8 mmol/L compared with non-users (in 2017: 51.7% and 19%, respectively). Among LLD users with prevalent ASCVD, 26.9% and 55% had, as recommended by current 2019 European guidelines, an LDL-C level of less than 1.4 mmol/L and less than 1.8 mmol/L, respectively, in 2017. CONCLUSIONS: LLD use and LDL-C levels are far from optimal in the Danish type 2 diabetes population and improvement in LLD use could reduce ASCVD events.

Changes in type 2 diabetes incidence and mortality associated with introduction of HbA1c as diagnostic option: A Danish 24-year population-based study.

BACKGROUND: In 2011, the World Health Organization began recommending glycated haemoglobin (HbA1c) as a measure for diagnosing type 2 diabetes (T2D). This initiative may have changed basic T2D epidemiology. Consequently, we examined time changes in T2D incidence and mortality during 1995-2018. METHODS: In this population-based cohort study, we included 415,553 individuals with incident T2D. We calculated annual age-standardized incidence rates of T2D. We examined HbA1c testing and used Poisson-regression to investigate all-cause mortality among the T2D patients and a matched comparison cohort from the general population over successive 3-year periods. FINDINGS: From 1995 to the 2012 introduction of HbA1c testing as a diagnostic option in Denmark, the annual standardized incidence rate (SIR) of T2D doubled, from 193 to 396 per 100,000 persons (4.1% increase annually). From 2012 onwards, the T2D incidence declined by 36%, reaching 253 per 100,000 persons in 2018 (5.7% decrease annually). This was driven by fewer patients starting treatment with an HbA1c measurement of <6·5% or without prior HbA1c testing. Mortality per 1,000 person-years following a T2D diagnosis decreased by 44% between 1995-1997 and 2010-2012, from 69 deaths to 38 deaths (adjusted mortality rate ratio: 0·55 (95% CI: 0·54-0·56)). After the low level during 2010-2012, mortality increased again by 27% to 48 per 1,000 person-years (95% CI: 46-50) by 2016-2018. INTERPRETATION: Our findings suggest that introducing HbA1c as a diagnostic option may have changed basic T2D epidemiology by leaving patients undiagnosed, that previously would have been diagnosed and treated. FUNDING: Aarhus University funded the study and had no further involvement.

Healthcare Resource Utilization and Costs for Empagliflozin Versus Glucagon-Like Peptide-1 Receptor Agonists in Routine Clinical Care in Denmark.

INTRODUCTION: The sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin has shown reductions in major adverse cardiac events similar to glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, evidence is limited about how these therapies compare regarding overall healthcare resource utilization and costs in routine clinical care. METHODS: We conducted a comparative cohort study based on linked prospective healthcare databases for the entire population of Denmark during 2015-2018. We included 13,747 new users of empagliflozin and 13,249 new users of GLP-1RAs. Propensity scores were applied to balance potential confounders across the two treatment groups through inverse probability treatment weighting (IPTW). We assessed directly referable costs per person-year associated with healthcare resource utilization (inpatient, emergency room, and outpatient clinic hospital care, primary care health services, and prescription medication costs at pharmacies) among drug initiators while on-treatment. RESULTS: The two IPTW cohorts were well balanced at baseline (median age 61 years, 60% men, diabetes duration 6.7 years, 19% with pre-existing ischemic heart disease, 8% with pre-existing cerebrovascular disease), with similar healthcare costs in the previous year. During follow-up, average on-treatment costs per person-year were very similar among empagliflozin and GLP-1 RA initiators for the following services: inpatient hospitalizations (13,565 DKK versus 13,275 DKK), hospital outpatient clinic visits (12,007 DKK versus 12,152 DKK), emergency room visits (370 DKK versus 399 DKK), and primary care services (4108 DKK versus 4302 DKK). Total costs for any prescription drugs were clearly lower for empagliflozin initiators than for GLP-1 RA initiators (8946 DKK versus 14,029 DKK). In sum, overall healthcare costs on-treatment were lower for empagliflozin initiators (38,995 DKK per person-year) than for GLP-1RA initiators (44,157 DKK per person-year). CONCLUSIONS: In this nationwide population-based cohort study, average healthcare costs after drug initiation and while on treatment were lower for empagliflozin initiators than for GLP-1RAs initiators, driven by lower drug costs. REGISTRATION: The study protocol and analysis plan have been registered on the website of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) ( http://www.encepp.eu/encepp/viewResource.htm?id=37726 , first protocol registration 4 June 2019), and on clinicaltrials.gov ( https://clinicaltrials.gov/ct2/show/NCT03993132 , first posted 20 June 2019).

Nationwide Trends in Cardiac Risk and Mortality in Patients With Incident Type 2 Diabetes: A Danish Cohort Study.

OBJECTIVE: Trends in cardiac risk and death have not been examined in patients with incident type 2 diabetes and no prior cardiovascular disease. Therefore, we aimed to examine trends in cardiac risk and death in relation to the use of prophylactic cardiovascular medications in patients with incident type 2 diabetes without prior cardiovascular disease. RESEARCH DESIGN AND METHODS: In this population-based cohort study, we included patients with incident type 2 diabetes between 1996 and 2011 through national health registries. Each patient was matched by age and sex with up to five individuals without diabetes from the general population. All individuals were followed for 7 years. RESULTS: We identified 209,311 patients with incident diabetes. From 1996-1999 to 2008-2011, the 7-year risk of myocardial infarction decreased from 6.9 to 2.8% (adjusted hazard ratio [aHR] 0.39 [95% CI 0.37-0.42]), cardiac death from 7.1 to 1.6% (aHR 0.23 [95% CI 0.21-0.24]), and all-cause death from 28.9 to 16.8% (aHR 0.68 [95% CI 0.66-0.69]). Compared with the general population, 7-year risk differences decreased from 3.3 to 0.8% for myocardial infarction, from 2.7 to 0.5% for cardiac death, and from 10.6 to 6.0% for all-cause death. Use of cardiovascular medications within ±1 year of diabetes diagnosis, especially statins (5% of users in 1996-1999 vs. 60% in 2008-2011), increased during the study period. CONCLUSIONS: From 1996 to 2011, Danish patients with incident type 2 diabetes and no prior cardiovascular disease experienced major reductions in cardiac risk and mortality. The risk reductions coincided with increased use of prophylactic cardiovascular medications.

Cardiovascular Events, Acute Hospitalizations, and Mortality in Patients With Type 2 Diabetes Mellitus Who Initiate Empagliflozin Versus Liraglutide: A Comparative Effectiveness Study.

Background In cardiovascular outcome trials, the sodium glucose cotransporter 2 inhibitor empagliflozin and glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide caused similar reductions in major adverse cardiac events (MACE). We compared clinical outcomes in routine clinical care. Methods and Results EMPLACE (Cardiovascular and Renal Outcomes, and Mortality in Danish Patients with Type 2 Diabetes Who Initiate Empagliflozin Versus GLP-1RA: A Danish Nationwide Comparative Effectiveness Study) is an ongoing nationwide population-based comparative effectiveness cohort study in Denmark. For the present study, we included 14 498 new users of empagliflozin and 12 706 new users of liraglutide, 2015 to 2018. Co-primary outcomes were expanded major adverse cardiac events (stroke, myocardial infarction, unstable angina, coronary revascularization, hospitalization for heart failure [HHF], or all-cause death); HHF or all-cause death; and first HHF or first initiation of loop-diuretic therapy. Secondary outcomes included all-cause hospitalization or death. We applied propensity score balancing and Cox regression to compute adjusted hazard ratios (aHRs) in on-treatment (OT) and intention-to-treat (ITT) analyses. Cohorts were well balanced at baseline (median age 61 years, 59% men, diabetes mellitus duration 6.6 years, 30% with preexisting cardiovascular disease). During mean follow-up of 1.1 years in OT and 1.5 years in ITT analyses, empagliflozin versus liraglutide was associated with a similar rate of expanded major adverse cardiac events (OT aHR, 1.02; 95% CI, 0.91-1.14; ITT aHR, 1.06; 95% CI, 0.96-1.17), and HHF or all-cause death (OT aHR, 0.97; 95% CI, 0.85-1.11; ITT aHR, 1.02; 95% CI, 0.91-1.14); and a decreased rate of a first incident HHF or loop-diuretic initiation (OT aHR, 0.80; 95% CI, 0.68-0.94; ITT aHR, 0.87; 95% CI, 0.76-1.00), and of all-cause hospitalization or death (OT aHR, 0.93; 95% CI, 0.89-0.98; ITT aHR, 0.93; 95% CI, 0.90-0.97). Conclusions Empagliflozin and liraglutide initiators had comparable rates of expanded major adverse cardiac events, and HHF or all-cause death, whereas empagliflozin initiators had a lower rate of a first HHF or loop-diuretic initiation.

Differences Between Randomized Clinical Trial Participants and Real-World Empagliflozin Users and the Changes in Their Glycated Hemoglobin Levels.

Importance: Use of the sodium-glucose cotransporter 2 inhibitor empagliflozin has increased substantially since 2015. Little is known about characteristics of real-world patients who use empagliflozin or about empagliflozin's effectiveness in reducing glycated hemoglobin (HbA1c) levels in routine clinical care. Objectives: To characterize real-world initiators of empagliflozin, to examine the proportion of initiators who would have been eligible for participation in phase 3 randomized clinical trials (RCTs) of empagliflozin, and to assess changes in HbA1c levels after empagliflozin initiation. Design, Setting, and Participants: This cross-sectional study used linked population-based medical databases containing complete information on redeemed prescriptions, laboratory tests, and diagnoses for all residents in Northern Denmark. A total of 7034 residents of Denmark who filled a first-time empagliflozin prescription from January 2014 to December 2018 were included. Data analysis was performed in August 2019. Exposure: Empagliflozin initiation. Main Outcomes and Measures: Proportion of real-world users ineligible for RCT inclusion and absolute reduction in HbA1c level 6 months after empagliflozin initiation. Results: Of 7034 first-time empagliflozin initiators (median [interquartile range] age, 61.50 [53.30-69.38] years; 4475 [63.6%] men), 3878 (55.1%) would have been ineligible for phase 3 RCT participation; frequent reasons were concurrent use of specific glucose-lowering drugs (1955 initiators [27.8%]), baseline HbA1c level outside the eligibility range (1772 [25.2%]), or presence of comorbidities (1067 initiators [15.3%]). Initiation of empagliflozin was associated with a mean HbA1c reduction of -0.91% (95% CI, -0.94% to -0.87%) after 6 months, similar to phase 3 RCT results. Real-world empagliflozin initiators who would have been eligible for RCT participation experienced slightly lower mean HbA1c reductions (-0.78%; 95% CI, -0.82% to -0.74%) compared with patients who would have been ineligible (-1.01%; 95% CI, -1.07% to -0.95%). Ineligible initiators had higher median (interquartile range) baseline HbA1c values than eligible initiators (8.5% [7.4% to 10.1%] vs 8.2% [7.6% to 9.8%]). Conclusions and Relevance: In this cross-sectional study, more than half of empagliflozin initiators exhibited clinical characteristics that would have led to ineligibility for the RCTs leading to the drug's approval. While the findings suggest that the efficacy of empagliflozin in reducing HbA1c levels translates into real-world effectiveness, further studies should examine clinical outcome effectiveness and drug safety in routine clinical care.

Changes in SGLT2i and GLP-1RA real-world initiator profiles following cardiovascular outcome trials: A Danish nationwide population-based study.

BACKGROUND: We investigated changes in clinical characteristics of SGLT2i and GLP-1RA real-world initiators in Denmark before/after landmark cardiovascular outcome trials. METHODS: We compared first-time SGLT2i (25,070) and GLP-1RA (14,671) initiators to initiators of DPP-4i (n = 34,079), a class without proven cardiovascular benefits. We used linked population-based healthcare data to examine initiation incidence, medication patterns, and pre-existing atherosclerotic cardiovascular disease (ASCVD) during 2014-2017. RESULTS: Nationwide incidence of SGLT2i initiators increased 3.6-fold (53/100,000 to 172/100,000 per year) vs. a 1.5-fold increase for GLP-1RA. DPP-4i initiation remained stable. From the end of 2015, SGLT2i was increasingly used as 2nd-line therapy, while medication patterns were much more stable for GLP-1RA. Among SGLT2i users, ASCVD increased slightly from 28% to 30%; age- and gender-adj. prevalence ratio (aPR) = 1.03 (95% CI:0.97-1.10). In contrast, among GLP-1RA initiators, baseline ASCVD declined from 29% to 27% (aPR: 0.90 (95% CI:0.84-0.97)), and in DPP-4i initiators from 31% to 29% (aPR: 0.91 (95% CI:0.88-0.96)). CONCLUSIONS: Following the EMPA-REG OUTCOME trial in 2015, SGLT2i have become increasingly used as 2nd-line treatment in everyday clinical practice, with only minor increases in patient proportions with ASCVD. For GLP-1RA, we observed more stable therapy lines and slightly decreasing ASCVD in new users despite the LEADER trial.

Clinical characteristics and glucose-lowering drug utilization among patients initiating liraglutide in Denmark: a routine clinical care prescription study.

Highlights This population-based real-world prescription study characterized all new users of liraglutide in northern Denmark from 2009 to 2015. More than half (57%) the patients had liraglutide prescribed as part of drug combinations outside the originally approved indications. Comorbidities or diabetes complications were present in most patients, with the highest prevalence observed among the 73% of initiators who would have been ineligible for the Liraglutide Effect and Action in Diabetes (LEAD) 1-5 trials that led to liraglutide registration, underscoring the need for further post-marketing studies.