Aims
To examine the comparative effectiveness of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium‐glucose cotransporter‐2 (SGLT2) inhibitors for select cardiovascular outcomes and to ...examine whether the relative risks varied across different patient subgroups in patients with type 2 diabetes.
Materials and Methods
We conducted a nationwide cohort study of patients with type 2 diabetes who initiated GLP‐1RAs or SGLT2 inhibitors between 2012 and 2018 in Taiwan. The study outcomes included myocardial infarction and total stroke, further classified into ischaemic or haemorrhagic stroke. We estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) for each outcome, comparing GLP‐1RAs with SGLT2 inhibitors using Cox proportional hazards models after 1:1 propensity‐score (PS) matching. We also examined if there was effect modification by age, underlying chronic kidney disease, or coexisting cardiovascular disease in prespecified subgroup analyses.
Results
Among 26 032 PS‐matched patients, GLP‐1RA initiators and SGLT2 inhibitor initiators showed similar risks of myocardial infarction (HR 0.99, 95% CI 0.65‐1.52), total stroke (HR 0.90, 95% CI 0.69‐1.17), ischaemic stroke (HR 0.86, 95% CI 0.65‐1.14) and haemorrhagic stroke (HR 0.88, 95% CI 0.63‐1.25). However, GLP‐1RA treatment was associated with an increased risk of total stroke (HR 1.76, 95% CI 1.06‐2.94) and ischaemic stroke (HR 1.88, 95% CI 1.09‐3.23) among patients with chronic kidney disease, but not among patients without chronic kidney disease. GLP‐1RA therapy seemed to have a lower risk of haemorrhagic stroke among patients with cardiovascular disease (HR 0.64, 95% CI 0.43‐0.97), but not in patients without cardiovascular disease.
Conclusions
Glucagon‐like peptide‐1 receptor agonists and SGLT2 inhibitors appeared to have comparable effectiveness with regard to several cardiovascular outcomes overall, but their comparative effectiveness may vary in certain patient subgroups.
Background
To compare the risks of major osteoporotic, vertebral, and non‐vertebral fractures between patients who discontinued anti‐osteoporosis medications.
Methods
We conducted a comparative ...effectiveness study with a nationwide population‐based cohort study design. Patients aged ≥50 years admitted between 2012 and 2015 for incident hip fractures and receiving denosumab or bisphosphonates with sufficient compliance for at least 1 year were included. Patients were categorized into persistent or non‐persistent denosumab or bisphosphonates users based on their subsequent use pattern. The main outcomes were subsequent hospitalizations for a major osteoporotic, vertebral or non‐vertebral fracture. Multivariate, time‐varying Cox proportional hazards model was used to evaluate the risk of major outcomes.
Results
Compared with persistent denosumab users, non‐persistent denosumab users had a significantly higher risk of major osteoporotic fractures (hazard ratio HR = 1.60; 95% confidence interval CI, 1.20–2.14), vertebral fractures (HR = 2.18; 95% CI, 1.46–3.24) and death (HR = 3.57; 95%CI, 2.63–4.84). However, the increased risk of fracture was not found in both persistent and non‐persistent bisphosphonates users. Noteworthy, the increased risk of vertebral fractures in non‐persistent denosumab users was more pronounced within 1 year post‐discontinuation (HR = 2.90; 95% CI, 1.77–4.74) and among patients who discontinued from 2‐year denosumab therapy (HR = 3.58; 95% CI, 1.74–7.40).
Discussion
Discontinuation of denosumab resulted in an increased risk of major osteoporotic fractures, especially vertebral fractures. The increased risk tends to reveal within 1 year post‐discontinuation and be greater after a longer treatment duration. Notably, only fracture with hospitalization was identified as our research outcome, the real risk of osteoporotic fracture post discontinuation is believed to be higher, especially for vertebral fracture.
Hypertension has been associated with Parkinson's disease (PD), but data on antihypertensive drugs and PD are inconclusive. We aim to evaluate antihypertensive drugs for an association with PD in ...hypertensive patients.
Hypertensive patients who were free of PD, dementia and stroke were recruited from 2005-2006 using Taiwan National Health Insurance Database. We examined the association between the use of calcium channel blockers (CCBs), angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and the incidence of PD using beta-blockers as the reference. Cox regression model with time-varying medication use was applied.
Among 65,001 hypertensive patients with a mean follow-up period of 4.6 years, use of dihydropyridine CCBs, but not non-dihydropyridine CCBs, was associated with a reduced risk of PD (adjusted hazard ratio aHR = 0.71; 95% CI, 0.57-0.90). Additionally, use of central-acting CCBs, rather than peripheral-acting ones, was associated with a decreased risk of PD (aHR = .69 55-0.87. Further decreased association was observed for higher cumulative doses of felodipine (aHR = 0.54 0.36-0.80) and amlodipine (aHR = 0.60 0.45-0.79). There was no association between the use of ACEIs (aHR = 0.80 0.64-1.00) or ARBs (aHR = 0.86 0.69-1.08) with PD. A potentially decreased association was only found for higher cumulative use of ACEIs (HR = 0.52 0.34-0.80) and ARBs (HR = 0.52 0.33-0.80).
Our study suggests centrally-acting dihydropyridine CCB use and high cumulative doses of ACEIs and ARBs may associate with a decreased incidence of PD in hypertensive patients. Further long-term follow-up studies are needed to confirm the potential beneficial effects of antihypertensive agents in PD.
Background and objective
The epidemiology of pediatric acquired demyelinating disorders remains to be clarified in many parts of Asia. We carry out this study to depict the epidemiology of pediatric ...multiple sclerosis (MS), neuromyelitis optica (NMO), and optic neuritis (ON) in Taiwan.
Methods
We conducted a retrospective nationwide population-based study using data from Taiwan’s National Health Insurance Research Database. Prevalent cases of pediatric MS and NMO during 2001–2015, and incident cases of pediatric MS, NMO, and ON during 2003–2015 were identified. The demographic features and comorbidities were investigated.
Results
We identified 403 MS, 42 NMO, and 1496 ON incident cases under the age of 20 during 2003–2015. The majority of pediatric MS (86.1%) and NMO (90.5%) patients were 10 years old or above. The incidence of MS and ON was relatively steady, while that of NMO increased prominently later during the study period. The average incidence of pediatric MS and NMO during 2011–2015 was 0.52 and 0.11 per 100,000 person-years, respectively. The female preponderance was evident for pediatric MS and NMO, and less so for pediatric ON. The most common autoimmune comorbidities for pediatric MS were thyrotoxicosis (1.0%) and systemic lupus erythematosus (0.7%).
Conclusion
The epidemiology of pediatric MS was largely stationary in Taiwan during 2001–2015, while the prevalence of pediatric NMO rose steeply during this period, probably reflecting better recognition of this clinical entity. Autoimmune comorbidities were uncommon for pediatric MS and NMO in Taiwan.
Genome-wide association studies (GWASs) have linked RRBP1 (ribosomal-binding protein 1) genetic variants to atherosclerotic cardiovascular diseases and serum lipoprotein levels. However, how RRBP1 ...regulates blood pressure is unknown.
To identify genetic variants associated with blood pressure, we performed a genome-wide linkage analysis with regional fine mapping in the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) cohort. We further investigated the role of the RRBP1 gene using a transgenic mouse model and a human cell model.
In the SAPPHIRe cohort, we discovered that genetic variants of the RRBP1 gene were associated with blood pressure variation, which was confirmed by other GWASs for blood pressure. Rrbp1- knockout (KO) mice had lower blood pressure and were more likely to die suddenly from severe hyperkalemia caused by phenotypically hyporeninemic hypoaldosteronism than wild-type controls. The survival of Rrbp1-KO mice significantly decreased under high potassium intake due to lethal hyperkalemia-induced arrhythmia and persistent hypoaldosteronism, which could be rescued by fludrocortisone. An immunohistochemical study revealed renin accumulation in the juxtaglomerular cells of Rrbp1-KO mice. In the RRBP1-knockdown Calu-6 cells, a human renin-producing cell line, transmission electron and confocal microscopy revealed that renin was primarily retained in the endoplasmic reticulum and was unable to efficiently target the Golgi apparatus for secretion.
RRBP1 deficiency in mice caused hyporeninemic hypoaldosteronism, resulting in lower blood pressure, severe hyperkalemia, and sudden cardiac death. In juxtaglomerular cells, deficiency of RRBP1 reduced renin intracellular trafficking from ER to Golgi apparatus. RRBP1 is a brand-new regulator of blood pressure and potassium homeostasis discovered in this study.
Sleep disturbances are common in women, especially during pregnancy. Previous studies have confirmed the importance of sleep disturbances as a risk factor of adverse pregnancy outcomes and the need ...for screening and treatment of inadequate sleep. These reports, however, did not examine health-related quality of life which may be affected by sleep long before adverse clinical consequences are detectable in women during pregnancy.
To examine the cross-sectional and longitudinal association between sleep and health-related quality of life in pregnant women.
A prospective observational study.
A university-affiliated hospital in Taiwan and participants’ homes.
A total of 164 pregnant women completed questionnaires and wore a wrist actigraphy monitor for 7 days each trimester.
Objective sleep was measured by actigraphy, subjective sleep was measured by the Pittsburgh Sleep Quality Index, and health-related quality of life was measured using the SF-12v2 questionnaire across three trimesters. Multiple linear regression analyses were performed to evaluate the cross-sectional and longitudinal associations between sleep and health-related quality of life.
Sixty-four (39.0%) women consistently had an average sleep efficiency<85% by actigraphy and 40 (24.4%) had a Pittsburgh Sleep Quality Index global score>5 in all three trimesters. Cross-sectionally, more actigraphic daytime sleep (p=0.04) and better subjective sleep quality (p<0.01) were associated with better physical health-related quality of life in first-trimester pregnant women. Better actigraphic sleep efficiency (p=0.04) and better subjective sleep quality (p<0.01) were associated with better mental health-related quality of life in second-trimester pregnant women. Longer actigraphic total nighttime sleep (p<0.01) and better subjective sleep quality (p<0.01) were associated with better mental health-related quality of life in third-trimester pregnant women. Longitudinally, first-trimester actigraphic total nighttime sleep (p<0.05) and subjective sleep quality (p<0.01) predicted mental health-related quality of life in the second and third trimester.
Sleep disturbances are a highly prevalent and persistent problem in pregnant women. Adequate sleep is essential for women at all pregnancy stages and improving nocturnal sleep quantity and quality in early gestation is of utmost importance for an optimal health-related quality of life later in pregnancy.
Melatonin exerts a wide range of effects among various tissues and organs. However, there is currently no study to investigate the genetic determinants of melatonin secretion. Here, we conducted a ...genome-wide association study (GWAS) for melatonin secretion using morning urine 6-hydroxymelatonin sulfate-to-creatinine ratio (UMCR). We initially enrolled 5000 participants from Taiwan Biobank in this study. After excluding individuals that did not have their urine collected in the morning, those who had history of neurological or psychiatric disorder, and those who failed to pass quality control, association of single nucleotide polymorphisms with log-transformed UMCR adjusted for age, sex and principal components of ancestry were analyzed. A second model additionally adjusted for estimated glomerular filtration rate (eGFR). A total of 2373 participants underwent the genome-wide analysis. Five candidate loci associated with log UMCR (P value ranging from 6.83 × 10
to 3.44 × 10
) encompassing ZFHX3, GALNT15, GALNT13, LDLRAD3 and intergenic between SEPP1 and FLJ32255 were identified. Similar results were yielded with further adjustment for eGFR. Interestingly, the identified genes are associated with circadian behavior, neuronal differentiation, motor disorders, anxiety, and neurodegenerative diseases. We conducted the first GWAS for melatonin secretion and identified five candidate genetic loci associated with melatonin level. Replication and functional studies are needed in the future.
Data regarding the nephrotoxicity of sofosbuvir (SOF) remain controversial. We compared the evolution of estimated glomerular filtration rate (eGFR) in patients with chronic HCV infection receiving ...SOF-based or SOF-free direct-acting antivirals (DAAs).
A total of 481 patients with compensated liver diseases and eGFR ≥30 ml/min/1.73m2, receiving SOF-based (n = 308) or SOF-free (n = 173) DAAs for 12 weeks, were prospectively enrolled. The eGFR was assessed from baseline to off-treatment week 24 using the chronic kidney disease (CKD)-epidemiology collaboration equation. Differences in the evolution of eGFR between regimens were compared by a generalized linear mixed-effects model. Multivariate analysis was performed for factors affecting eGFR evolution.
Patients receiving SOF-based DAAs experienced a significant on-treatment decline in eGFR (adjusted slope coefficient difference: −1.24 ml/min/1.73m2/month; 95% CI −1.35 to −1.13; p <0.001) and a significant off-treatment improvement (adjusted slope coefficient difference: 0.14 ml/min/1.73m2/month; 95% CI 0.08 to 0.21; p = 0.004) compared to patients receiving SOF-free DAAs. Multivariate analysis showed age per 1-year increase (adjusted slope coefficient difference: −0.05 ml/min/1.73m2/month; 95% CI −0.05 to −0.04; p <0.001), SOF-based DAAs (adjusted slope coefficient difference: −0.33 ml/min/1.73m2/month; 95% CI −0.49 to −0.17; p <0.001), and CKD stage (adjusted slope coefficient difference: −1.44 ml/min/1.73m2/month; 95% CI −1.58 to −1.30; p <0.001 for stage 3 vs. 1, and −3.59 ml/min/1.73m2/month; 95% CI −3.88 to −3.30; p <0.001 for stage 2 vs. 1) were independent factors affecting eGFR evolution from baseline to off-treatment week 24.
Patients receiving SOF-based DAAs exhibited a quadratic trend, with eGFR worsening on treatment and improving off treatment. Increasing age, SOF-based DAAs, and more advanced baseline CKD stage are independently associated with a decline in eGFR in patients with HCV receiving DAAs.
While the efficacy of sofosbuvir for the treatment of hepatitis C virus is clear, data regarding its possible nephrotoxicity are controversial. Herein, we showed that sofosbuvir worsened on-treatment kidney function but led to an off-treatment improvement. Our findings suggest that treating physicians should be alert to risk factors for kidney dysfunction before initiating direct-acting antiviral treatment for patients with hepatitis C virus infection.
NCT04047680
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•Patients receiving SOF-based DAAs exhibit a quadratic trend, with eGFR worsening on treatment and improving off treatment.•Patients receiving SOF-free DAAs have a linear trend with eGFR improving on and off treatment.•Increasing age, use of SOF-based DAAs, and more advanced baseline CKD stage are independent risk factors of eGFR decline.
Summary Background Extracorporeal life-support as an adjunct to cardiac resuscitation has shown encouraging outcomes in patients with cardiac arrest. However, there is little evidence about the ...benefit of the procedure compared with conventional cardiopulmonary resuscitation (CPR), especially when continued for more than 10 min. We aimed to assess whether extracorporeal CPR was better than conventional CPR for patients with in-hospital cardiac arrest of cardiac origin. Methods We did a 3-year prospective observational study on the use of extracorporeal life-support for patients aged 18–75 years with witnessed in-hospital cardiac arrest of cardiac origin undergoing CPR of more than 10 min compared with patients receiving conventional CPR. A matching process based on propensity-score was done to equalise potential prognostic factors in both groups, and to formulate a balanced 1:1 matched cohort study. The primary endpoint was survival to hospital discharge, and analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00173615. Findings Of the 975 patients with in-hospital cardiac arrest events who underwent CPR for longer than 10 min, 113 were enrolled in the conventional CPR group and 59 were enrolled in the extracorporeal CPR group. Unmatched patients who underwent extracorporeal CPR had a higher survival rate to discharge (log-rank p<0·0001) and a better 1-year survival than those who received conventional CPR (log rank p=0·007). Between the propensity-score matched groups, there was still a significant difference in survival to discharge (hazard ratio HR 0·51, 95% CI 0·35–0·74, p<0·0001), 30-day survival (HR 0·47, 95% CI 0·28–0·77, p=0·003), and 1-year survival (HR 0·53, 95% CI 0·33–0·83, p=0·006) favouring extracorporeal CPR over conventional CPR. Interpretation Extracorporeal CPR had a short-term and long-term survival benefit over conventional CPR in patients with in-hospital cardiac arrest of cardiac origin. Funding National Science Council, Taiwan.
Prior observational studies have suggested that fluoroquinolone use may be associated with more than 2-fold increased risk of aortic aneurysm or aortic dissection (AA/AD). These studies, however, did ...not fully consider the role of coexisting infections and the risk of fluoroquinolones relative to other antibiotics.
To estimate the risk of AA/AD associated with infections and to assess the comparative risk of AA/AD associated with fluoroquinolones vs other antibiotics with similar indication profiles among patients with the same types of infections.
This nested case-control study identified 21 651 176 adult patients from a nationwide population-based health insurance claims database from January 1, 2009, to November 30, 2015. Each incident case of AA/AD was matched with 10 control individuals by age, sex, and follow-up duration in the database using risk-set sampling. Analysis of the data was conducted from April 2019 to March 2020.
Infections and antibiotic use within a 60-day risk window before the occurrence of AA/AD.
Conditional logistic regression was used to estimate the odds ratios (ORs) and 95% CIs comparing infections for which fluoroquinolones are commonly used with no infection within a 60-day risk window before outcome occurrence, adjusting for baseline confounders and concomitant antibiotic use. The adjusted ORs comparing fluoroquinolones with antibiotics with similar indication profiles within patients with indicated infections were also estimated.
A total of 28 948 cases and 289 480 matched controls were included (71.37% male; mean SD age, 67.41 15.03 years). Among these, the adjusted OR of AA/AD for any indicated infections was 1.73 (95% CI, 1.66-1.81). Septicemia (OR, 3.16; 95% CI, 2.63-3.78) and intra-abdominal infection (OR, 2.99; 95% CI, 2.45-3.65) had the highest increased risk. Fluoroquinolones were not associated with an increased AA/AD risk when compared with combined amoxicillin-clavulanate or combined ampicillin-sulbactam (OR, 1.01; 95% CI, 0.82-1.24) or with extended-spectrum cephalosporins (OR, 0.88; 95% CI, 0.70-1.11) among patients with indicated infections. The null findings for fluoroquinolone use remained robust in different subgroup and sensitivity analyses.
These results highlight the importance of accounting for coexisting infections while examining the safety of antibiotics using real-world data; the findings suggest that concerns about AA/AD risk should not deter fluoroquinolone use for patients with indicated infections.
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