bluuebunny/crossref_metadata_2025_split huggingface dataset:
GLP1-RA versus metformin as first-line therapy for achieving glycemic control and risk-factor management - a one-year nationwide cohort study
Authors: Soerensen K K , Torp-Pedersen C , Pedersen-Bjerregaard U , Zareini B 
Published: November 2023

Abstract

Background
Glucagon-like peptide 1 receptor agonist (GLP1-RA) reduces cardiovascular events in patients with long standing diabetes. We hypothesized that treatment early during diabetes could be beneficial.

Purpose
The aim was to compare one-year effects of GLP1-RA and metformin as first-line glucose-lowering therapy on glycemic control, adherence, kidney function, and cholesterol levels.

Methods
Using the Danish nationwide registers, we included all first-line users of monotherapy with GLP1-RA or metformin between 2018-2021, who had information on glycated hemoglobin (HbA1c) maximum one year prior to baseline and a measured HbA1c level above 41 mmol/mol. The outcomes were one-year change in HbA1c category, adherence to therapy, avoidance of add-on glucose lowering drugs, as well as absolute change in HbA1c, creatinine, and cholesterol levels. Targeted likelihood maximum estimation with ensemble Superlearning was used to estimate the average treatment effects.

Results
A total of 40,987 individuals were included, of which 870 were prescribed GLP1-RA and 40,117 were prescribed metformin. After adjusting for age, sex, income, education, degree of urbanization, baseline HbA1c levels, comorbidities, and concomitant medication, GLP1-RA users had an one-year absolute decrease in HbA1c (ATE: -3.84 mmol/mol, 95% CI: -5.36;.-2.33), and HDL (ATE: -0.03 mmol/L, 95% CI: -0.06;-0.01), an absolute increase in creatinine (ATE: 2.89 μmol/L, 95% CI: 0.07;4.82), and no difference in low-density lipoprotein cholesterol (ATE: 0.11 mmol/L [95% CI: -0.03;0.24]), total lipoprotein cholesterol (ATE: 0.13 mmol/L [95% CI: -0.03;0.29]), triglycerides (ATE: 0.02 mmol/L [95% CI: -0.25;0.30]), non-adherence (RR: 1.05 [95% CI: 0.75;1.46]), and add-on therapy (RR: 1.04 [95% CI: 0.75;1.44]), compared to metformin users.

Conclusion
First line use of GLP1-RA was associated with a clear one-year reduction of HbA1c and a very small increase in creatinine. Future studies are needed to show whether this translates to a clinical benefit.
Duration of type 2 diabetes mellitus is associated with third-degree atrioventricular block - A Danish nationwide registry study
Authors: Haxha S , Soerensen K K , Haugaard S B , Ruwald M H , Halili A , Philbert B T , Koeber L , Gislason G H , Torp-Pedersen C , Bang C N 
Published: November 2023

Abstract

Introduction
Type 2 diabetes mellitus (T2DM) is associated with third-degree atrioventricular block, but whether duration of T2DM is an important factor of the association is unknown.

Aim
To investigate the association between duration of T2DM and third-degree atrioventricular block.

Method
This nested case–control study, based on nation-wide Danish cohort registries, included patients older than 18 years, diagnosed with third-degree atrioventricular block between 1 July 1995 and 31 December 2018. Five controls, from the risk set of each case of third-degree atrioventricular block, were matched on age and sex to fit a conditional logistic regression with time-dependent exposure and time-dependent covariates. Duration of T2DM was split into four groups: 0–5 years, 6–10 years, 11–15 years, and &gt;15 years.

Results
We included 24 177 cases with third-degree atrioventricular block who were matched 1:5 on sex and birth year with 120 915 controls without third-degree atrioventricular block. Median age was 73.8 years, 62% were males in both cases and controls, whereas 19% of cases and 9.7% of controls had T2DM respectively. After adjusting for atrioventricular nodal blocking agents and comorbidities known to be associated with third-degree atrioventricular block, patients with T2DM duration 0–5 years, 6–10 years, 11-15 years, and &gt;15 years had a higher hazard ratio of third-degree atrioventricular block of 1.24 (95% CI 1.16-1.33), 1.41 (95% CI 1.31-1.52), 1.79 (95% CI 1.64-1.95), and 2.20 (95% CI 2.01-2.40), respectively, compared to patients with no T2DM (Figure 1).

Conclusion
This study shows a stepwise increase in the hazard ratio of third-degree atrioventricular block along with duration of T2DM, which is independent of atrioventricular nodal blocking agents and comorbidities known to be associated with third-degree atrioventricular block.Figure 1
The gender gap in prescription pattern of Sodium-Glucose Cotransporter 2 inhibitors in patients with Type 2 Diabetes and Coronary Artery Disease
Authors: Hammer A , Hofer F , Kazem N , Koller L , Steinacher E , Baumer U , Niessner A , Sulzgruber P 
Published: November 2023

Abstract

Background
Type 2 diabetes mellitus (T2DM) is a major risk factor for the development of coronary artery disease (CAD), which is the leading cause of morbidity and mortality in T2DM patients. In this regard, sodium-glucose 2 cotransporter (SGLT2) inhibitors have been proven to not only reduce the glycemic burden but additionally lower the risk of major adverse cardiovascular events in T2DM patients with established CAD or at high risk for CAD. However, previous studies have not dealt with SGLT2 inhibitor prescription under real-world conditions, especially if SGLT2 inhibitor therapy is sex-independently utilized in such patients.

Methods
Patients with T2DM and CAD admitted to a tertiary academic center between 01/2014 and 04/2020 were identified by searching electronic health records. Patient characteristics and data on antidiabetic therapy at discharge were assessed.

Results
The present analysis included 1498 patients, with a median age of 70 years and 36.3% of them being female. Overall, only 17.2% of the entire cohort received an SGLT2 inhibitor, with an increasing prescription trend during the observation period. Interestingly, the prescription rate of SGLT2 inhibitors showed significant differences between males and females with a significantly lower intention for prescription in women (18.7% vs. 13.3%, p=0.008), despite having comparable patient characteristics. Women who did not receive an SGLT2 inhibitor tended to present more frequently with chronic kidney disease, however only 43 women presented with an estimated glomerular filtration rate of &lt;30ml/min/1.73m2, which does not explain the observed general gender gap. Furthermore, in a regression analysis male participants were found to have a significantly higher probability of SGLT2i prescription, illustrated as an adjusted odds ratio of 1.44 (CI 95% 1.022-2.022; p =0.037) compared to women.

Conclusion
SGLT2i are potentially underutilized in female patients with CAD and T2DM, despite an overall increasing prescription trend during the observation period. Reasons for withholding therapy could not be objectified. The present data indicate a major need to increase awareness of guideline-directed therapy, especially in female T2DM patients with established CAD.
Biochemical profiles and risk of cardiovascular events in patients withType 2 Diabetes: implications for choice of novel antihyperglycemic therapy
Authors: Malik M E , Zahir D , Garred C H , Jensen J , Holt A , Andersson C , Fosboel E , Koeber L , Schou M 
Published: November 2023

Abstract

Background
Guidelines on type 2 diabetes (T2D) recommend targeting patients at greater risk of heart failure with sodium-glucose cotransporter-2 inhibitors (SGLT2-i) and patients at greater risk of cardiovascular ischemic events with glucagon-like peptide-1 receptor agonists (GLP1-RA) or SGLT2-i. It is currently unclear whether distinct biochemical profiles are more or less associated with the occurrence of heart failure or a cardiovascular ischemic event.

Purpose
To investigate the risk of the first occurring event of either heart failure or a cardiovascular ischemic event associated with different biochemical profiles in newly diagnosed T2D patients without cardiovascular disease.

Methods
From Danish nationwide registers, we identified all patients newly diagnosed with T2D who were free of cardiovascular disease (heart failure, ischemic heart disease, peripheral artery disease, and previous stroke), from 2013-2021. Patients &lt;40 years, and patients without a registered blood test within three months prior to the T2D diagnosis, were excluded. The absolute 5-year risk of the first occurring event of either heart failure or a cardiovascular ischemic event, was calculated for patients with different levels of three biochemical markers that are known to be associated with cardiovascular disease: 1) HbA1c 2) low-density lipoprotein (LDL); and 3) estimated glomerular filtration rate (eGFR) calculated from serum creatinine.

Results
Of the 81,095 patients included in the study, 53% were male and the median age was 60 years [interquartile range 52-69]. For all pre-defined biochemical profiles—HbA1c below or above 8%, LDL below or above 4 mmol/L, and eGFR below or above 60ml/min/1.73m2—the absolute 5-year risk of a cardiovascular ischemic event was greater than the risk of heart failure (risk ratio ranging from 2.3–4.2), as the first occurring event following the diagnosis of T2D. The highest risk of heart failure was observed in those with moderately to severely reduced eGFR (&lt;60 ml/min/1.73m2).

Conclusions
Among patients newly diagnosed with T2D and free of cardiovascular disease, different biochemical profiles of HbA1c, LDL, and eGFR, were all associated with a higher risk of an ischemic cardiovascular event as the first occurring event following T2D diagnosis, as opposed to heart failure.Flowchart of patient selectionCumulative incidence of CIE Vs. HF
GLP1 receptor agonists exhibit antioxidant and anti-inflammatory properties in human heart tissue via the canonical GLP1 receptor expression through a AMPK-mediated pathway
Authors: Cordeanu E M , Qureshi A W , Mroueh A , Mazzucotelli J P , Stephan D , Schini-Kerth V 
Published: November 2023

Abstract

Background
Clinical research has demonstrated that glucagon-like peptide-1 receptor (GLP1R) agonists (GLP1RA) can decrease the occurrence of major cardiovascular events in diabetic patients, regardless of their glycemic control. However, a significant challenge in understanding the positive effects of GLP1RA has been the lack of knowledge regarding the specific cellular types that express GLP1R. Despite the established cardiovascular benefits of GLP1RA, previous studies have been unable to confirm the expression of GLP1R in the heart.

Aim
The study aimed to investigate the expression and function of GLP1R in heart tissue.

Methods
We collected human cardiac tissue samples from 30 patients who underwent left ventricle (LV) biopsies (n=21) or right atrial (RA) appendage closure (n=9) at a university hospital. Gene expression levels were assessed using RT-qPCR, protein levels by Western blot analysis, in situ tissue localization of proteins by immunofluorescence (IF) staining, and the level of oxidative stress using dihydroethidium.

Results
LV biopsies and RA appendages showed a substantial heterogeneity in GLP1R mRNA levels. GLP1R mRNA levels exhibited a positive correlation with IL1B, IL6, TNFα, CCL2, CD68, ACE1, AT1R, and VCAM1 mRNA levels, but a negative correlation with NOS3 mRNA levels. High GLP1R expression in both RA appendages and LV biopsies was associated with increased oxidative stress levels, which were mitigated by the antioxidant N-acetylcysteine (NAC), NADPH oxidase inhibitor (VAS-2870), ACE inhibitor (perindoprilat), AT1R antagonist (losartan), TNF-α receptor neutralizing antibody (infliximab) and by GLP1R agonists (liraglutide and semaglutide) with inhibitory effects amounting to about 50-60 %. Exendin, a GLP1R antagonist reversed the effect of liraglutide and semaglutide which accounted for a receptor-mediated antioxidant effect. H-89, a PKA inhibitor equally reversed liraglutide and semaglutide effect on ROS generation suggesting a canonical GLP1R mediated effect involving the AMPK pathway.

Conclusion
These findings indicate that human cardiac GLP1R expression levels are correlated to low-grade inflammation and endothelial dysfunction. Increased expression levels of GLP1R were associated with higher levels of oxidative stress sensitive to GLP1RA in a canonical GLP1R AMPK-mediated manner. Therefore, the cardiovascular beneficial effects of GLP1RA might be attributable to their antioxidant and anti-inflammatory properties, specifically within the cardiac system.
Lower risks of new-onset hip fracture risks in users of sodium glucose cotransporter 2 (SGLT2) inhibitors versus users of dipeptidyl peptidase-4 (DPP4) inhibitors: a propensity score-matched analysis
Authors: Chou O H I , Zhou J , Satti D I , Lin K , Lee S , Wong W T , Wai A K C , Liu T , Cheung B M Y , Jing F , Tse G 
Published: November 2023

Abstract

Purpose
This study aimed to compare the effects of sodium glucose cotransporter 2 inhibitors (SGLT2I) and dipeptidyl peptidase-4 inhibitors (DPP4I) on new-onset hip fractures.

Methods
This was a retrospective population-based cohort study including type-2 diabetes mellitus patients treated with either SGLT2I or DPP4I between January 1st 2015 and December 31st 2020 in Hong Kong. The primary outcome was new-onset hip fracture and the secondary outcome was all-cause mortality. Propensity score matching (1:1 ratio) using the nearest neighbour search was performed. Univariable and multivariable Cox regression were applied to identify significant predictors. Competing risks models and multiple approaches using the propensity score were performed.

Results
This cohort included 56393 patients with type-2 diabetes mellitus (median age: 62.1 years old [interquantile range, IQR]: 54.2-71.1; 57.45% males), of which 20432 patients ([incidence rate, IR]: 36.23%) used SGLT2I and 35961 patients (IR: 63.77%) used DPP4I. After the 1:1 propensity score matching, 449 (IR: 1.09%) patients had hip fractures, and 2012 patients (IR: 4.92%) died. SGLT2I was associated with significantly lower risks of hip fractures after adjusting for the demographics, past comorbidities, non-SGLT2I/DPP4I medications and laboratory results (hazard ratio: 0.55; 95% confidence interval: 0.42-0.89; P=0.0036). The results were consistent in the competing risk models and the different propensity matching approaches.

Conclusions
SGLT2I was associated with lower risks of new-onset hip fractures after propensity score matching and adjustments.Figure 1
Amiodarone and the risk for pulmonary fibrosis. A Danish nationwide study
Authors: Al-Abbasi B , Haxha S , Storgaard A , Kober L , Gislason G , Torp-Pedersen C H , Bang C 
Published: November 2023

Abstract

Background
Amiodarone may cause pulmonary fibrosis. However, very few studies have investigated this possible association. This study will evaluate whether amiodarone is associated with pulmonary fibrosis, and furthermore, if there is an exposure-response relationship.

Method and results
Using Danish national patient registries, we conducted an observational population-based study. Individuals diagnosed with pulmonary fibrosis were identified between 1996 and 2020 using ICD codes and then included in a nested case-control study, where cases were matched with 5 controls.
The exposure to amiodarone was defined by dispensed amiodarone recipes from the national prescription registry. Cox regression analysis was used to derive the crude hazard ratio (HR) and the confidence interval (CI). The analyses were also adjusted and stratified for pre-specified comorbidities to derive multivariate Hazard ratio. Furthermore, we analysed the outcome in respect to amiodarone exposure time (&lt;3 months, 3-6 months, 6-12 months, 1-3 years, 3-5 years, over 5 years) and also in respect to the cumulative dosage.
A total of 27 948 cases diagnosed with pulmonary fibrosis over the 24 years period of study in Danish population were matched with 139 740 controls. The average age was 69 years and 45% was females.
We found that amiodarone treatment was associated with significant risk of pulmonary fibrosis (HR: 4.20, 95%CI: [3.83-4.60], p&lt;0.001). After adjusting for comorbidities including hypertension, diabetes mellitus, asthma, chronic obstructive pulmonary disease, ischemic heart disease, heart failure, stroke, any cancer, liver failure, chronic kidney disease, and alcohol, the association remained significant (HR:2.55, 95%CI: [2.30-2.82], p&lt;0.001) (Figure 1), and its remained also significant after excluding COPD patients from the population (HR: 3.93, 95%CI: [3.50-4.40], p&lt;0.001). Finally, the treatment exposure relationship, 0-3 months (HR:2.34, 95%CI [1.82-3.02], p&lt;0.001), and over 5 years (HR: 5.90, 95%CI [4.56-7.65], p&lt;0.001) (figure 2), and dose response relationship, 0-18gm (HR: 2.48, 95%CI: [1.93-3.18], p&lt;0.001), 120-240gm (HR: 4.34, 95%CI: [3.46-5.45], p&lt;0.001), and over 840gm (HR: 7.06, 95%CI: [3.08-16.15], p&lt;0.001) (figure 3).

Conclusion
Amiodarone use was found associated with an independent incident pulmonary fibrosis, 4-fold crude risk and with a more than 2-fold hazard already within the first 3 months of treatment. The association showed also a dose- and duration relationship, where larger doses and longer treatment were associated with higher hazard of pulmonary fibrosis.
Optimal adherence threshold to non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation to reduce the risk of thromboembolism and death
Authors: Grymonprez M , Steurbaut S , Capiau A , Vauterin D , Van Vaerenbergh F , Mehuys E , Boussery K , De Backer T L , Lahousse L 
Published: November 2023

Abstract

Background
Poor adherence to non-vitamin K antagonist oral anticoagulants (NOACs) may raise thromboembolic risks in patients with atrial fibrillation (AF). However, the minimal adherence to maintain the protective effects of NOACs is currently unknown.

Purpose
To investigate thresholds of NOAC adherence in association with thromboembolic and mortality risks.

Methods
Using two Belgian nationwide healthcare databases, AF patients ≥45 years old with ≥1 NOAC prescription claim between January 1st, 2013 and January 1st, 2019 were identified. Patients were followed from NOAC initiation until the first occurrence of the investigated outcome, treatment discontinuation (&gt;60-day supply gap), switch to VKAs, death, emigration or end of the study period. Adherence was measured using the proportion of days covered (PDC) after one year of treatment. Inverse probability weighted Cox regression (adjusting for 39 confounding covariates) was used to investigate outcomes (identified using International Classification of Diseases-coded hospital discharge diagnoses and medical procedure codes) between NOAC users with a one-year PDC of 100% (reference group) and NOAC users with lower PDCs.

Results
A total of 92,111 newly-treated AF patients were included during a mean follow-up of 2.7 ± 1.4 years (250,750 person-years of on-treatment follow-up). The proportions of persistent NOAC users with a PDC of 100%, 95-99%, 90-94%, 85-89%, 80-84% and &lt;80% after one year of treatment were 62.7%, 17.4%, 9.5%, 5.1%, 2.8% and 2.5%, respectively. Compared to NOAC users with a one-year PDC of 100%, significantly higher risks of stroke or systemic embolism were observed among NOAC users with PDCs of 85-89% (adjusted hazard ratio (aHR) 1.35, 95% confidence interval (CI) (1.19-1.54)), 80-84% (aHR 1.31, 95%CI (1.08-1.58)) and &lt;80% (aHR 1.64, 95%CI (1.34-2.01)), while no significant differences were observed among NOAC users with one-year PDCs of 95-99% (aHR 1.02, 95%CI (0.94-1.12)) or 90-94% (aHR 1.06, 95%CI (0.95-1.18)) after multivariable adjustment. Significantly higher risks of all-cause mortality (aHR 1.09, 95%CI (1.01-1.17) and major or clinically relevant non-major bleeding (aHR 1.10, 95%CI (1.04-1.16) were observed with decreasing levels of NOAC adherence, starting from NOAC users with a one-year PDC of 90-94% versus 100%. Findings were similar with once-daily and twice-daily dosed NOACs.

Conclusion
Lower adherence to NOAC treatment is associated with increased risks of thromboembolism, all-cause mortality and bleeding. For adequate stroke prevention in AF, the optimal adherence threshold to NOAC treatment should be at least 90%, irrespective of the dosing regimen of NOACs.Figure 1
Outcomes with oral anticoagulation resumption or discontinuation after an anticoagulation-related event in patients with atrial fibrillation
Authors: Denas G , Gennaro N , Ferroni E , Zorzi M , Pagliani L , Pengo V 
Published: November 2023

Abstract

Background
There are uncertainties on the resumption of anticoagulation therapy in patients with non-valvular atrial fibrillation who experience a thrombotic or haemorrhagic event while on oral anticoagulation.

Purpose
We assessed the cumulative incidence of recurrent stroke, major bleeding and all-cause mortality associated with restarting antithrombotic treatment, after stroke or major bleeding during anticoagulation therapy for atrial fibrillation.

Methods
We included anticoagulated patients with atrial fibrillation that were discharged (2013-2020) from hospital for stroke, intracranial haemorrhage (ICH), and major bleeding. To adjust for competing risk of death and reduce confounding, we started the follow up after 120-days blanking period, counting events in patients resuming oral anticoagulation versus those that did not. Risks of all-cause mortality, thromboembolism, intracranial haemorrhage, and major bleeding were estimated with multivariable Cox proportional hazard models and propensity score to adjust for differences in baseline characteristics.

Results
1029 patients (mean age 77 years) were included in the final cohort: 23% were ischemic stroke, 18% were ICH, and 59% major bleeding; of these, 77% resumed anticoagulation. Among patients with stroke as the index event (92% resumed anticoagulation) the cumulative incidence of events was significantly lower in patients resuming therapy (HR 0.2, 95%CI 0.1-0.4, p&lt;0.01). In patients with ICH (64% resumed therapy) the cumulative incidence of events was lower in patients resuming anticoagulation (HR 0.4, 95%CI 0.2-0.7, p&lt;0.01). Same was true for patients with major bleeding, with patients resuming therapy (76%), experiencing fewer events (HR 0.5, 95%CI 0.2-0.7, p&lt;0.01). In the multivariable analysis considering age, sex and propensity score as covariates, resumption of anticoagulation significantly reduced the cumulative event rate (HR 0.5, 95%CI 0.4-0.6, p&lt;0.01).

Conclusion
In patients with atrial fibrillation who experienced an anticoagulation-related event, resuming oral anticoagulation was associated with better outcomes for all-cause mortality and subsequent events as compared with patients who did not resume treatment.Stacked Area Charts and Cox regression