Fluoroquinolones and the risk of severe hypoglycaemia among sulphonylurea users: Population-based cohort study.

AIM: Fluoroquinolone-related hypoglycaemia is rare but may become clinically relevant in individuals at high baseline hypoglycaemic risk, such as patients with diabetes using sulphonylureas. Our population-based cohort study assessed whether fluoroquinolones are associated with an increased risk of severe hypoglycaemia compared with amoxicillin among patients treated with sulphonylureas. MATERIALS AND METHODS: Using the UK's Clinical Practice Research Datalink Aurum linked to hospitalization and vital statistics data, we assembled a base cohort of patients who initiated second-generation sulphonylureas (1998-2020). The study cohort included patients initiating either fluoroquinolones or amoxicillin while on sulphonylureas. Using an intent-to-treat exposure definition, we assessed the 30-day risk of severe hypoglycaemia (hospitalization with or death because of hypoglycaemia) associated with fluoroquinolones compared with amoxicillin. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of severe hypoglycaemia after 1:5 matching on previous sulphonylurea use and propensity scores. Secondary analyses were stratified by demographics and glycated haemoglobin. RESULTS: Overall, 143 417 patients initiated fluoroquinolones (n = 13 123) or amoxicillin (n = 130 294) while on sulphonylureas. Compared with amoxicillin, fluoroquinolones were not associated with the risk of severe hypoglycaemia (HR, 1.17; 95% CI, 0.91-1.50). Fluoroquinolones were associated with an increased risk in patients <65 years (HR, 2.90; 95% CI, 1.41-5.97) but not in those ≥65 years (HR, 1.03; 95% CI, 0.79-1.35) in stratified analyses. There was no evidence of effect modification by sex or glycated haemoglobin. CONCLUSIONS: In patients using second-generation sulphonylureas, fluoroquinolones were not associated with an increased risk of severe hypoglycaemia compared with amoxicillin. An increased risk among younger adults is possible.

The Associations Between Sleep and Externalizing and Internalizing Problems in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: Empirical Findings, Clinical Implications, and Future Research Directions.

Sleep problems are common in youth with attention-deficit/hyperactivity disorder (ADHD). Externalizing and internalizing problems contribute to dysfunction in youth with ADHD and are amplified by disrupted sleep. This objective of this article is to synthesize empirical studies that examined the associations between sleep and internalizing or externalizing problems in individuals with ADHD. The main findings are that sleep problems precede, predict, and significantly contribute to the manifestation of internalizing and externalizing behavior problems among children and adolescents with ADHD. Clinicians should assess sleep and integrate sleep interventions into the management of youth with ADHD.

Pharmacologic Heterogeneity and Risk of Severe Hypoglycemia with Concomitant Use of Sulfonylureas and DPP-4 Inhibitors: Population-Based Cohort Study.

Dipeptidyl peptidase-4 inhibitors (DPP-4i) interact with sulfonylureas to increase their risk of hypoglycemia. Our population-based study assessed whether intraclass pharmacologic heterogeneity among sulfonylureas (long- vs. short-acting) and DPP-4i (peptidomimetic vs. non-peptidomimetic) modifies this interaction. We conducted a cohort study using the UK's Clinical Practice Research Datalink Aurum linked to hospitalization and vital statistics data. We assembled a cohort of patients initiating sulfonylureas (2007-2020). Using a time-varying exposure definition, we assessed the risk of severe hypoglycemia (hospitalization with or death due to hypoglycemia) associated with (i) concomitant use of long-acting sulfonylureas (glimepiride and glibenclamide) with DPP-4i compared with concomitant use of short-acting sulfonylureas (gliclazide and glipizide) with DPP-4i; and (ii) concomitant use of sulfonylureas with peptidomimetic DPP-4i (saxagliptin and vildagliptin) compared with concomitant use of sulfonylureas with non-peptidomimetic DPP-4i (sitagliptin, linagliptin, and alogliptin). Time-dependent Cox models estimated confounder-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Our cohort included 196,138 sulfonylurea initiators. During a median follow-up of 6 years, 8,576 events of severe hypoglycemia occurred. Compared with concomitant use of short-acting sulfonylureas with DPP-4i, concomitant use of long-acting sulfonylureas with DPP-4i was not associated with the risk of severe hypoglycemia (adjusted HR: 0.87, 95% CI: 0.65-1.16). Compared with concomitant use of sulfonylureas with non-peptidomimetic DPP-4i, concomitant use of sulfonylureas with peptidomimetic DPP-4i was also not associated with the risk of severe hypoglycemia (HR: 0.96, 95% CI: 0.76-1.22). Intra-class pharmacologic heterogeneity did not modify the association between concomitant use of sulfonylureas (short- vs. long-acting) and DPP-4i (peptidomimetic vs. non-peptidomimetic) and the risk of severe hypoglycemia.

Concomitant Use of Sulfonylureas and ß-Blockers and the Risk of Severe Hypoglycemia Among Patients With Type 2 Diabetes: A Population-Based Cohort Study.

OBJECTIVE: The hypoglycemic potential of ß-blockers among users of sulfonylureas, drugs that strongly increase the risk of this potentially fatal adverse effect, is not well understood. Our population-based cohort study assessed the potential association between concomitant use of sulfonylureas and ß-blockers versus use of sulfonylureas alone and the risk of severe hypoglycemia. RESEARCH DESIGN AND METHODS: Using the U.K. Clinical Practice Research Datalink Aurum, we included patients initiating sulfonylureas between 1998 and 2020, excluding those with ß-blocker use in the past 6 months. Time-dependent Cox models estimated hazard ratios (HRs) with 95% CIs of severe hypoglycemia (hospitalization with or death resulting from hypoglycemia; ICD-10 codes E16.0, E16.1, and E16.2) associated with current concomitant use of sulfonylureas and ß-blockers compared with current sulfonylurea use alone, adjusted for baseline confounders. We also compared current concomitant use of sulfonylureas and non-cardioselective versus cardioselective ß-blockers. RESULTS: Our cohort included 252,869 initiators of sulfonylureas (mean age 61.3 years; 43% female). Median follow-up was 7.9 years. The crude incidence rate of severe hypoglycemia was 7.8 per 1,000 per year. Concomitant use of sulfonylureas and ß-blockers was associated with an increased risk of severe hypoglycemia compared with sulfonylurea use alone (HR 1.53; 95% CI 1.42-1.65). There was no difference in the risk between concomitant use of sulfonylureas and noncardioselective ß-blockers and concomitant use of sulfonylureas and cardioselective ß-blockers (HR 0.95; 95% CI 0.74-1.24). CONCLUSIONS: ß-blockers could further increase the risk of severe hypoglycemia when used concurrently with sulfonylureas. ß-blocker cardioselectivity did not seem to play a major role in this regard.

Effectiveness and Safety of Direct Oral Anticoagulants Among Octogenarians with Venous Thromboembolism: An International Multidatabase Cohort Study.

BACKGROUND: The effects of direct oral anticoagulants (DOACs) among octogenarian patients with venous thromboembolism remains poorly understood. To address this knowledge gap, our study aimed to assess the effectiveness and safety of DOACs compared to vitamin K antagonists (VKAs) among octogenarians with venous thromboembolism. METHODS: We conducted an international cohort study using administrative health care databases from Québec, Canada, and Germany. We assembled 2 population-based cohorts of octogenarians with incident venous thromboembolism initiating treatment with DOACs or VKAs. The study period spanned from January 2012 to the most recent date of data availability (Québec: December 2016; Germany: December 2019). Using an as-treated exposure definition, we compared use of DOACs to use of VKAs, applying inverse probability of treatment weighting based on high-dimensional propensity scores to balance exposure groups. Cox proportional hazards models estimated site-specific hazard ratios (HRs) and 95% confidence intervals (CIs) of recurrent venous thromboembolism, major bleeding, and all-cause mortality. The results were meta-analyzed using random-effects models. RESULTS: Overall, our study included 6737 octogenarians with venous thromboembolism (Québec: n = 2556; Germany: n = 4181) who initiated use of DOACs (n = 3778) or VKAs (n = 2959). When compared to VKAs, DOACs were associated with similar risks of recurrent venous thromboembolism (weighted HR, 0.80; 95% CI, 0.43-1.46; I2 = 0.00), major bleeding (weighted HR, 0.96; 95% CI, 0.57-1.63; I2 = 0.59), and all-cause mortality (weighted HR, 1.04; 95% CI, 0.81-1.34; I2 = 0.00). CONCLUSIONS: Among octogenarians with venous thromboembolism, DOACs showed a comparable effectiveness and safety compared to VKAs. Our results support the use of DOACs in this high-risk group.

The Associations Between Sleep and Externalizing and Internalizing Problems in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: Empirical Findings, Clinical Implications, and Future Research Directions.

Sleep problems are common in youth with attention-deficit/hyperactivity disorder (ADHD). Externalizing and internalizing problems contribute to dysfunction in youth with ADHD and are amplified by disrupted sleep. This objective of this article is to synthesize empirical studies that examined the associations between sleep and internalizing or externalizing problems in individuals with ADHD. The main findings are that sleep problems precede, predict, and significantly contribute to the manifestation of internalizing and externalizing behavior problems among children and adolescents with ADHD. Clinicians should assess sleep and integrate sleep interventions into the management of youth with ADHD.