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To assess the association between the use of sodium glucose cotransporter 2 (SGLT2) inhibitors and seven serious adverse events of current concern. Register based cohort study. Sweden and Denmark from July 2013 to December 2016. A propensity score matched cohort of 17 213 new users of SGLT2 inhibitors (dapagliflozin, 61%; empagliflozin, 38%; canagliflozin, 1%) and 17 213 new users of the active comparator, glucagon-like peptide 1 (GLP1) receptor agonists. The primary outcomes were lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis, as identified from hospital records. Hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazards models. Use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation (incidence rate 2.7 1.1 events per 1000 person years, hazard ratio 2.32, 95% confidence interval 1.37 to 3.91) and diabetic ketoacidosis (1.3 0.6, 2.14, 1.01 to 4.52) but not with bone fracture (15.4 13.9, 1.11, 0.93 to 1.33), acute kidney injury (2.3 3.2, 0.69, 0.45 to 1.05), serious urinary tract infection (5.4 6.0, 0.89, 0.67 to 1.19), venous thromboembolism (4.2 4.1, 0.99, 0.71 to 1.38) or acute pancreatitis (1.3 1.2, 1.16, 0.64 to 2.12). In this analysis of nationwide registers from two countries, use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation and diabetic ketoacidosis, but not with other serious adverse events of current concern.

AbstractObjectiveTo assess the association between use of sodium-glucose co-transporter 2 (SGLT2) inhibitors and risk of serious renal events in data from routine clinical practice.DesignCohort study using an active comparator, new user design and nationwide register data.SettingSweden, Denmark, and Norway, 2013-18.ParticipantsCohort of 29 887 new users of SGLT2 inhibitors (follow-up time: dapagliflozin 66.1%; empagliflozin 32.6%; canagliflozin 1.3%) and 29 887 new users of an active comparator, dipeptidyl peptidase-4 inhibitors, matched 1:1 on the basis of a propensity score with 57 variables. Mean follow-up time was 1.7 (SD 1.0) years.ExposuresSGLT2 inhibitors versus dipeptidyl peptidase-4 inhibitors, defined by filled prescriptions and analysed according to intention to treat.Main outcome measuresThe main outcome was serious renal events, a composite including renal replacement therapy, death from renal causes, and hospital admission for renal events. Secondary outcomes were the individual components of the main outcome.ResultsThe mean age of the study population was 61.3 (SD 10.5) years; 11 108 (19%) had cardiovascular disease, and 1974 (3%) had chronic kidney disease. Use of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors, was associated with a reduced risk of serious renal events (2.6 events per 1000 person years versus 6.2 events per 1000 person years; hazard ratio 0.42 (95% confidence interval 0.34 to 0.53); absolute difference −3.6 (–4.4 to −2.8) events per 1000 person years). In secondary outcome analyses, the hazard ratio for use of SGLT2 inhibitors versus dipeptidyl peptidase-4 inhibitors was 0.32 (0.22 to 0.47) for renal replacement therapy, 0.41 (0.32 to 0.52) for hospital admission for renal events, and 0.77 (0.26 to 2.23) for death from renal causes. In sensitivity analyses in each of the Swedish and Danish parts of the cohort, the model was further adjusted for glycated haemoglobin and estimated glomerular filtration rate (Sweden and Denmark) and for blood pressure, body mass index, and smoking (Sweden only); in these analyses, the hazard ratio moved from 0.41 (0.26 to 0.66) to 0.50 (0.31 to 0.81) in Sweden and from 0.42 (0.32 to 0.56) to 0.55 (0.41 to 0.74) in Denmark.ConclusionsIn this analysis using nationwide data from three countries, use of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors, was associated with a significantly reduced risk of serious renal events.

AbstractObjectiveTo investigate the cardiovascular effectiveness of sodium glucose cotransporter 2 (SGLT2) inhibitors in routine clinical practice.DesignCohort study using data from nationwide registers and an active-comparator new-user design.SettingDenmark, Norway, and Sweden, from April 2013 to December 2016.Participants20 983 new users of SGLT2 inhibitors and 20 983 new users of dipeptidyl peptidase 4 (DPP4) inhibitors, aged 35-84, matched by age, sex, history of major cardiovascular disease, and propensity score.Main outcome measuresPrimary outcomes were major cardiovascular events (composite of myocardial infarction, stroke, and cardiovascular death) and heart failure (hospital admission for heart failure or death due to heart failure). Secondary outcomes were the individual components of the cardiovascular composite and any cause death. In the primary analyses, patients were defined as exposed from treatment start throughout follow-up (analogous to intention to treat); additional analyses were conducted with an as-treated exposure definition. Cox regression was used to estimate hazard ratios.ResultsMean age of the study cohort was 61 years, 60% were men, and 19% had a history of major cardiovascular disease. Of the total 27 416 person years of follow-up in the SGLT2 inhibitor group, 22 627 (83%) was among patients who initiated dapagliflozin, 4521 (16%) among those who initiated empagliflozin, and 268 (1%) among those who initiated canagliflozin. During follow-up, 467 SGLT2 inhibitor users (incidence rate 17.0 events per 1000 person years) and 662 DPP4 inhibitor users (18.0) had a major cardiovascular event, whereas 130 (4.7) and 265 (7.1) had a heart failure event, respectively. Hazard ratios were 0.94 (95% confidence interval 0.84 to 1.06) for major cardiovascular events and 0.66 (0.53 to 0.81) for heart failure. Hazard ratios were consistent among subgroups of patients with and without history of major cardiovascular disease and with and without history of heart failure. Hazard ratios for secondary outcomes, comparing SGLT2 inhibitors with DPP4 inhibitors, were 0.99 (0.85 to 1.17) for myocardial infarction, 0.94 (0.77 to 1.15) for stroke, 0.84 (0.65 to 1.08) for cardiovascular death, and 0.80 (0.69 to 0.92) for any cause death. In the as-treated analyses, hazard ratios were 0.84 (0.72 to 0.98) for major cardiovascular events, 0.55 (0.42 to 0.73) for heart failure, 0.93 (0.76 to 1.14) for myocardial infarction, 0.83 (0.64 to 1.07) for stroke, 0.67 (0.49 to 0.93) for cardiovascular death, and 0.75 (0.61 to 0.91) for any cause death.ConclusionsIn this large Scandinavian cohort, SGLT2 inhibitor use compared with DPP4 inhibitor use was associated with reduced risk of heart failure and any cause death, but not with major cardiovascular events in the primary intention-to-treat analysis. In the additional as-treated analyses, the magnitude of the association with heart failure and any cause death became larger, and a reduced risk of major cardiovascular events that was largely driven by the cardiovascular death component was observed. These data help inform patients, practitioners, and authorities regarding the cardiovascular effectiveness of SGLT2 inhibitors in routine clinical practice.

This cohort study involving nationwide Danish registry data showed no significantly higher risk of adverse pregnancy outcomes among women exposed to quadrivalent HPV vaccination during pregnancy than among women without vaccination. Human papillomavirus (HPV) vaccines are recommended for all girls and women 9 to 26 years of age, 1 , 2 and more than 72 million girls and women have been vaccinated worldwide. 3 Although HPV vaccination is not recommended in pregnancy, a number of women will be inadvertently vaccinated early in the first trimester of unplanned or unrecognized pregnancies. 4 , 5 However, data on the safety of vaccination during pregnancy are limited. 6 The clinical trials of HPV vaccines did not include women who were known to be pregnant. Consequently, analyses of safety during pregnancy that were based on data from clinical trials focused mainly . . .

A recent study in a Medicaid population indicated an increased risk of cardiovascular death with azithromycin. The current study in a population in Denmark indicates no increase in risk. In a related Perspective, the FDA reviews its reasons for adding a warning of increased risk to the drug label. Azithromycin is a macrolide antibiotic agent primarily used for the treatment of lower and upper respiratory infections and some sexually transmitted infections. This commonly used agent is considered to be generally free of serious adverse effects, including cardiac toxicity. 1 – 5 A recent observational study, however, showed that use of azithromycin was associated with a risk of death from cardiovascular causes that was 2 to 3 times as high as the risk associated with no use of antibiotics and the risk associated with amoxicillin treatment. 6 Given that certain other macrolides are known to prolong the QT interval and therefore are thought . . .

AbstractObjectiveTo investigate whether oral fluoroquinolone use is associated with an increased risk of aortic aneurysm or dissection.DesignNationwide historical cohort study using linked register data on patient characteristics, filled prescriptions, and cases of aortic aneurysm or dissection.SettingSweden, July 2006 to December 2013.Participants360 088 treatment episodes of fluoroquinolone use (78%ciprofloxacin) and propensity score matched comparator episodes of amoxicillin use (n=360 088).Main outcome measuresCox regression was used to estimate hazard ratios for a first diagnosis of aortic aneurysm or dissection, defined as admission to hospital or emergency department for, or death due to, aortic aneurysm or dissection, within 60 days from start of treatment.ResultsWithin the 60 day risk period, the rate of aortic aneurysm or dissection was 1.2 cases per 1000 person years among fluoroquinolone users and 0.7 cases per 1000 person years among amoxicillin users. Fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection (hazard ratio 1.66 (95% confidence interval 1.12 to 2.46)), with an estimated absolute difference of 82 (95% confidence interval 15 to 181) cases of aortic aneurysm or dissection by 60 days per 1 million treatment episodes. In a secondary analysis, the hazard ratio for the association with fluoroquinolone use was 1.90 (1.22 to 2.96) for aortic aneurysm and 0.93 (0.38 to 2.29) for aortic dissection.ConclusionsIn a propensity score matched cohort, fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection. This association appeared to be largely driven by aortic aneurysm.

Bjarke Feenstra and colleagues identify common variants at six loci associated with general or MMR vaccine–related febrile seizures. The two loci specifically associated with MMR-related febrile seizures harbor the interferon-stimulated gene IFI44L and the measles virus receptor gene CD46 . Febrile seizures represent a serious adverse event following measles, mumps and rubella (MMR) vaccination. We conducted a series of genome-wide association scans comparing children with MMR-related febrile seizures, children with febrile seizures unrelated to vaccination and controls with no history of febrile seizures. Two loci were distinctly associated with MMR-related febrile seizures, harboring the interferon-stimulated gene IFI44L (rs273259: P = 5.9 × 10 −12 versus controls, P = 1.2 × 10 −9 versus MMR-unrelated febrile seizures) and the measles virus receptor CD46 (rs1318653: P = 9.6 × 10 −11 versus controls, P = 1.6 × 10 −9 versus MMR-unrelated febrile seizures). Furthermore, four loci were associated with febrile seizures in general, implicating the sodium channel genes SCN1A (rs6432860: P = 2.2 × 10 −16 ) and SCN2A (rs3769955: P = 3.1 × 10 −10 ), a TMEM16 family gene ( ANO3 ; rs114444506: P = 3.7 × 10 −20 ) and a region associated with magnesium levels (12q21.33; rs11105468: P = 3.4 × 10 −11 ). Finally, we show the functional relevance of ANO3 (TMEM16C) with electrophysiological experiments in wild-type and knockout rats.

Although some data have linked proton pump inhibitor (PPI) use to risk of depression and anxiety, there are no studies investigating this safety issue in children. This study investigated the association between PPI use and risk of depression and anxiety in children. We conducted a nationwide register‐based cohort study in Sweden, July 1, 2007, to December 31, 2016. Following matching on age and propensity score, we included 29,320 pairs of PPI initiators and noninitiators among children aged 7–17 years old. The primary analysis examined the risk of incident depression and anxiety, a composite outcome defined as a diagnosis of depression, anxiety, or a prescription for an antidepressant. Children who initiated PPI use had higher hazards for risk of depression and anxiety compared with noninitiators (hazard ratios [HRs], 2.61; 95% confidence interval [CI], 2.32–2.94). In analyses of the timing of depression and anxiety onset after PPI initiation, the HRs were 3.71 (95% CI, 2.17–6.34) for 1–30 days, 3.47 (95% CI, 2.33–5.18) for 31–90 days, 2.71 (2.04–3.60) for 91–180 days, 2.52 (2.00–3.16) for 181–365 days, and 2.34 (1.94–2.82) for 366–730 days. Significant associations were observed across all age groups. The magnitude of the association increased with longer duration of PPI use (p for trend < 0.0001). The association was consistent through all sensitivity analyses, including high‐dimensional propensity score matching (HR, 2.31, 95% CI, 2.05–2.61). PPI use was associated with increased risk of depression and anxiety in children. Further investigation is warranted to confirm or refute this potential association.

In this registry-based historical cohort study, ondansetron exposure in pregnancy was not associated with significantly increased risks of spontaneous abortion, stillbirth, any major birth defect, preterm delivery, or low birth weight. Nausea and vomiting are common during pregnancy, affecting more than half of all pregnant women. 1 , 2 Whereas these symptoms can be managed conservatively in most pregnant women, 10 to 15% receive drug treatment. 1 , 3 Because nausea and vomiting manifest in early pregnancy, with onset between 3 and 8 weeks of gestation and with peak symptoms in weeks 7 to 12 in most cases, 1 , 2 , 4 drug treatment often coincides with the period during which the fetus is most susceptible to teratogenic effects. Among the drugs available for the treatment of nausea and vomiting during pregnancy, 1 the 5-hydroxytryptamine type 3 receptor . . .

► We identified 2608 narcolepsy cases in 6 EU countries between 2000 and 2010. ► After pandemic vaccination, incidence rates increased in Finland, Sweden and Denmark. ► In Denmark, the increase did not follow high pandemic vaccination coverage. ► In Italy, the Netherlands and the United Kingdom no increased rates were seen. In August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification. We used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000–2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom. Overall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95% CI: 0. 90–0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women>men) and around 60 years of age. In the age group 5–19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95% CI: 1.1–3.1) in Denmark, 6.4 (95% CI: 4.2–9.7) in Finland and 7.5 (95% CI: 5.2–10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time. The results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail.