Cardiovascular Effects Of Incretin-Based Antihyperglycemic Drugs Relative To Treatment Alternatives In Older Adults

Randomized placebo-controlled trials have examined the cardiovascular effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), but limited data exist on the comparative incidence relative to therapeutic alternatives, including sulfonylureas (SU) and thiazolidinediones (TZD). In this study we therefore examined the comparative incidence of cardiovascular events with DPP-4i compared with relevant comparators using a new-user design. In recent years the use of SU was constant but DPP-4i use increased with a corresponding decrease in TZD use. Using hospitalization for heart failure (HF) as a positive control outcome we explored the use of calendar time as an instrumental variable (IV) and compared this approach to an active comparator new-user study comparing DPP-4i versus TZD. Using 2007-2013 US Medicare claims data, we identified two new user cohort pairs – DPP-4i versus SU and DPP-4i versus TZD. Since TZDs are contraindicated in patients with HF, we further excluded patients with diagnoses of HF or related conditions for the DPP-4i versus TZD analyses. Using propensity score-weighted survival analysis methods accounting for competing risk by death, we estimated hazard ratios (HR), risk differences (RD) and 95% confidence intervals (CI) for myocardial infarction (MI), stroke, HF hospitalization, and a composite outcome (MI, stroke, or all-cause mortality). For the IV analyses, we examined the IV strength and estimated RD for HF using Kaplan-Meier curves. The magnitude of RD per 100 patients for MI, stroke and HF hospitalization was <1 at one year after initiation with DPP-4i versus SU or TZD. The IV analysis compared patients initiating treatment during October 2010 to December 2013 versus January 2008 to May 2010 resulting in IV strength 40%. The 1- and 2-year RD of HF using the IV approach (scaled by IV-strength) and propensity score weighting were between 0 and -1 per 100 patients. Our well-controlled population based study suggests no increased short-term CV risk with DPP-4i relative to comparators. Both IV and propensity score-weighted approaches indicate lesser risk of HF hospitalizations among DPP-4i vs TZD initiators. The use of calendar time as an IV in settings where real-world market dynamics lead to profound changes in treatments is worth consideration.Doctor of Philosoph

Effect of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors on colorectal cancer incidence and its precursors

Incretin-based antihyperglycemic therapies increase intestinal mucosal expansion and polyp growth in mouse models. We aimed to evaluate the effect of dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonists (GLP-1ra) initiation on colorectal cancer incidence

Burden of asthma exacerbations and health care utilization in pediatric patients with asthma in the US and England.

BACKGROUND: Data on asthma burden in pediatric patients are limited; this real-world study investigated exacerbation frequency and health care resource utilization (HCRU) in pediatric asthma patients from the US and England. METHODS: Data from pediatric patients (aged 6-17 years) in the Optum claims database (US) or Clinical Practice Research Datalink with linkage to Hospital Episode Statistics (England) were analyzed. Patients were categorized into four hierarchical groups: treated asthma (patients with ≥1 baseline asthma medication), severe asthma (plus Global Initiative for Asthma Step 4/5), severe refractory asthma ([SRA] plus ≥2 baseline severe asthma exacerbations), and eosinophilic SRA (SRA plus blood eosinophil count ≥150 cells/µL). Exacerbation frequency and HCRU during the 12 months postindex were described. RESULTS: Of 151 549 treated asthma patients in the US, 18 086 had severe asthma, 2099 SRA, and 109 eosinophilic SRA. There were 32 893 treated asthma patients in England, of whom 2711 had severe asthma, 265 SRA, and 8 eosinophilic SRA. In the 12 months postindex, ≥1 exacerbation occurred in 12.4% and 10.8% of patients with severe asthma, and 32.6% and 42.6% with SRA in the US and England, respectively. The proportions of patients with ≥1 asthma hospitalization in the 30 days after the first asthma exacerbation were 2.7% and 4.4% (treated), 3.5% and 8.2% (severe asthma), and 6.0% and 16.8% (SRA) in the US and England, respectively. CONCLUSION: This study provides insights into current asthma management practices in the US and England and indicates that some patients with severe disease have an unmet need for effective management

More realistic power estimation for new user, active comparator studies: an empirical example: New User Design Power Estimation Considerations

Pharmacoepidemiologic studies are often expected to be sufficiently powered to study rare outcomes, but there is sequential loss of power with implementation of study design options minimizing bias. We illustrate this using a study comparing pancreatic cancer incidence after initiating dipeptidyl-peptidase-4 inhibitors (DPP-4i) versus thiazolidinediones or sulfonylureas

Comparison of diagnostic evaluations for cough among initiators of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: Diagnostic Workup in Antihypertensive Drug Initiators

Differential diagnostic evaluation associated with a drug may bias effect estimates due to an increased detection of preclinical outcomes. Persistent cough is a common side effect with angiotensin-converting enzyme inhibitors (ACEI) and we hypothesized that ACEI initiators would undergo more diagnostic evaluations, potentially leading to diagnosis of preclinical lung cancer. We compared the incidence of cough-related diagnostic evaluations and lung cancer among ACEI versus angiotensin receptor blockers (ARB) initiators

Treatment of human astrocytoma U87 cells with silicon dioxide nanoparticles lowers their survival and alters their expression of mitochondrial and cell signaling proteins

Recent evidence suggests silicon dioxide micro- and nanoparticles induce cytotoxic effects on lung cells. Thus, there is an increasing concern regarding their potential health hazard. Nevertheless, the putative toxicity of nanoparticles in mammalian cells has not yet been systematically investigated. We previously noted that several metallic oxide nanoparticles exert differential cytotoxic effects on human neural and nonneural cells. Therefore, we hypothesized that silicon dioxide nanoparticles induce cytotoxicity in U87 cells by lowering their survival by decreasing cell survival signaling and disturbing mitochondrial function. To investigate this hypothesis, we determined the activities of the key mitochondrial enzymes, citrate synthase and malate dehydrogenase, in astrocytoma U87 cells treated with silicon dioxide nanoparticles. In addition, we studied the expression of the mitochondrial DNA-encoded proteins, cytochrome C oxidase II and nicotinamide adenine dinucleotide (NADPH) dehydrogenase subunit 6, and cell signaling pathway protein extracellular signal-regulated kinase (ERK) and phosphorylated ERK in treated U87 cells. The activated form of ERK controls cell growth, differentiation, and proliferation. In parallel, we determined survival of U87 cells after treating them with various concentrations of silicon dioxide nanoparticles. Our results indicated that treatment with silicon dioxide nanoparticles induced decreases in U87 cell survival in a dose-related manner. The activities of citrate synthase and malate dehydrogenase in treated U87 cells were increased, possibly due to an energetic compensation in surviving cells. However, the expression of mitochondrial DNA-encoded cytochrome C oxidase subunit II and NADH dehydrogenase subunit 6 and the cell signaling protein ERK and phosphorylated ERK were altered in the treated U87 cells, suggesting that silicon dioxide nanoparticles induced disruption of mitochondrial DNA-encoded protein expression, leading to decreased mitochondrial energy production and decreased cell survival/proliferation signaling. Thus, our results strongly suggest that the cytotoxicity of silicon dioxide nanoparticles in human neural cells implicates altered mitochondrial function and cell survival/proliferation signaling

Assessing the Impact of Propensity Score Estimation and Implementation on Covariate Balance and Confounding Control Within and Across Important Subgroups in Comparative Effectiveness Research

Researchers are often interested in estimating treatment effects in subgroups controlling for confounding based on a propensity score (PS) estimated in the overall study population

Framework for the Synthesis of Non-Randomised Studies and Randomised Controlled Trials: A Guidance on Conducting a Systematic Review and Meta-Analysis for Healthcare Decision Making

Introduction: High-quality randomised controlled trials (RCTs) provide the most reliable evidence on the comparative efficacy of new medicines. However, non-randomised studies (NRS) are increasingly recognised as a source of insights into the real-world performance of novel therapeutic products, particularly when traditional RCTs are impractical or lack generalisability. This means there is a growing need for synthesising evidence from RCTs and NRS in healthcare decision making, particularly given recent developments such as innovative study designs, digital technologies and linked databases across countries. Crucially, however, no formal framework exists to guide the integration of these data types. Objectives and Methods: To address this gap, we used a mixed methods approach (review of existing guidance, methodological papers, Delphi survey) to develop guidance for researchers and healthcare decision-makers on when and how to best combine evidence from NRS and RCTs to improve transparency and build confidence in the resulting summary effect estimates. Results: Our framework comprises seven steps on guiding the integration and interpretation of evidence from NRS and RCTs and we offer recommendations on the most appropriate statistical approaches based on three main analytical scenarios in healthcare decision making (specifically, ‘high-bar evidence’ when RCTs are the preferred source of evidence, ‘medium,’ and ‘low’ when NRS is the main source of inference). Conclusion: Our framework augments existing guidance on assessing the quality of NRS and their compatibility with RCTs for evidence synthesis, while also highlighting potential challenges in implementing it. This manuscript received endorsement from the International Society for Pharmacoepidemiology

Assessing the Impact of Propensity Score Estimation and Implementation on Covariate Balance and Confounding Control Within and Across Important Subgroups in Comparative Effectiveness Research

PURPOSE: Researchers are often interested in estimating treatment effects in subgroups controlling for confounding based on a propensity score (PS) estimated in the overall study population. OBJECTIVE: To evaluate covariate balance and confounding control in sulfonylurea (SU) versus metformin (MET) initiators within subgroups defined by cardiovascular disease history (CVD) comparing an overall PS with subgroup-specific PSs implemented by 1:1 matching and stratification. METHODS: We analyzed younger patients from a US insurance claims database and older patients from two Medicare (Humana Medicare Advantage, fee-for-service Medicare Parts A, B and D) datasets. Confounders and risk factors for acute myocardial infarction (AMI) were included in an overall PS and subgroup PSs with and without CVD. Covariate balance was assessed using the average standardized absolute mean difference (ASAMD). RESULTS: Compared to crude estimates, ASAMD across covariates was improved 70–94% for stratification for Medicare cohorts and 44–99% for the younger cohort, with minimal differences between overall and subgroup-specific PSs. With matching, 75–99% balance improvement was achieved regardless of cohort and PS, but with smaller sample size. Hazard Ratios within each CVD subgroup differed minimally among PS and cohorts. CONCLUSION: Both overall PSs and CVD subgroup-specific PSs achieved good balance on measured covariates when assessing the relative association of diabetes monotherapy with nonfatal MI. PS matching generally led to better balance than stratification, but with smaller sample size. Our study is limited insofar as crude differences were minimal, suggesting that the new user, active comparator design identified patients with some equipoise between treatments