Understanding the Gap Between Efficacy in Randomized Controlled Trials and Effectiveness in Real-World Use of GLP-1 RA and DPP-4 Therapies in Patients With Type 2 Diabetes.

OBJECTIVE: The objective of this study was to estimate and explain the gap between clinical efficacy and real-world (RW) effectiveness of type 2 diabetes medications. RESEARCH DESIGN AND METHODS: This mixed-methods quasi-experimental study used retrospective claims (Optum/Humedica) to compare the change in HbA1c of RW patients with type 2 diabetes 12 months after starting a glucagon-like peptide 1 receptor agonist (GLP-1 RA) or dipeptidyl peptidase 4 (DPP-4) inhibitor with published findings from randomized controlled trials (RCTs) evaluating these drugs. Selected RW patients were similar to RCT patients, and regression analysis was used in the RW data to adjust for differences between poorly adherent and adherent patients to explain why RCT and RW findings may differ. RESULTS: RW patients initiating a GLP-1 RA (n = 221) or a DPP-4 (n = 652) experienced smaller reductions in HbA1c (GLP-1 RA: -0.52% [-6 mmol/mol], DPP-4: -0.51% [-6 mmol/mol])than reported in RCTs (-1.30% [-14 mmol/mol] from seven GLP-1 RA RCTs, n = 2,600; -0.68% [-8 mmol/mol] from four DPP-4 RCTs, n = 1,889). Baseline HbA1c, additional medications, and adherence were significant explanatory factors in the RW HbA1c change. Modeled estimates of RCT efficacy (-1.04% GLP-1 RA [-12 mmol/mol], -0.69% DPP-4 [-8 mmol/mol]) were within the RCTs' reported range (GLP-1 RA: -0.84% to -1.60% [-9 to -18 mmol/mol], DPP-4: -0.47% to -0.90% [-5 to -10 mmol/mol]). Poor medication adherence accounted for approximately three-fourths of the gap between RW and expected RCT results (gap = 0.51% [6 mmol/mol] GLP-1 RA; 0.18% [3 mmol/mol] DPP-4). CONCLUSIONS: Poor medication adherence is primarily why RW effectiveness is significantly less than RCT efficacy, suggesting an urgent need to effectively address adherence among patients with type 2 diabetes.

Drug-Drug Interaction Associated with Mold-Active Triazoles among Hospitalized Patients.

The majority of hospitalized patients receiving mold-active triazoles are at risk of drug-drug interactions (DDIs). Efforts are needed to increase awareness of DDIs that pose a serious risk of adverse events. Triazoles remain the most commonly utilized antifungals. Recent developments have included the mold-active triazoles (MATs) itraconazole, voriconazole, and posaconazole, which are first-line agents for the treatment of filamentous fungal infections but have the potential for DDIs. This objective of this study was to evaluate the prevalence of triazole DDIs. Hospitalized U.S. adults with MAT use were identified in the Cerner HealthFacts database, which contained data from over 150 hospitals (2005 to 2013). The severities of DDIs with MATs were categorized, using drug labels and the drug information from the Drugdex system (Thompson Micromedex), into four groups (contraindicated, major, moderate, and minor severity). DDIs of minor severity were not counted. A DDI event was considered to have occurred if the following two conditions were met: (i) the patient used at least one drug with a classification of at least a moderate interaction with the MAT during the hospitalization and (ii) there was a period of overlap between the administration of the MAT and that of the interacting drug of at least 1 day. A total of 6,962 hospitalizations with MAT use were identified. Among them, 88% of hospitalizations with voriconazole use, 86% of hospitalizations with itraconazole use, and 93% of hospitalizations with posaconazole use included the use of a concomitant interacting drug. A total of 68% of hospitalizations with posaconazole use, 34% of hospitalizations with itraconazole use, and 20% of hospitalizations with voriconazole use included the use of at least one drug with a DDI of contraindicated severity. A total of 83% of hospitalizations with posaconazole use, 61% of hospitalizations with itraconazole use, and 82% of hospitalizations with voriconazole use included the use of at least one drug that resulted in a severe DDI. The findings of this study demonstrate that a majority of hospitalized patients receiving MAT are at risk for severe drug-drug interactions and highlight the need for antifungal stewardship.

Brentuximab vedotin compared with other therapies in relapsed/refractory Hodgkin lymphoma post autologous stem cell transplant: median overall survival meta-analysis.

OBJECTIVE: This meta-analysis compared the median overall survival (mOS) of brentuximab vedotin reported in the pivotal phase 2 study with published results of other therapies for the treatment of relapsed/refractory (R/R) Hodgkin lymphoma (HL) post autologous stem cell transplant (ASCT). RESEARCH DESIGN AND METHODS: A systematic literature review identified studies that reported survival outcomes following conventional/experimental therapies in R/R HL patients, with ≥50% having failed ≥1 ASCT. Kaplan-Meier curves were used to reconstruct individual patient level survival data. Patients were grouped by treatment type and reconstructed data were used to estimate the mOS. Censored median regression modeling was used to compare mOS in each group with the mOS in the pivotal brentuximab vedotin trial. All patients in the pivotal trial had undergone ASCT, therefore a sensitivity analysis was conducted among studies with a 100% post-ASCT patient population. RESULTS: The mOS reported for brentuximab vedotin was 40.5 (95% CI 30.8-NA) compared with 26.4 months (95% CI 23.5-28.5) across all 40 studies identified (n = 2518 excluding the brentuximab vedotin trial) (p < 0.0001). The difference in mOS between brentuximab vedotin and chemotherapy, allogeneic stem cell transplant (allo-SCT), and other therapies, was 17.7 (95% CI 10.6-24.7; p < 0.0001), 12.5 (95% CI 8.2-16.9; p < 0.0001), and 15.2 months (95% CI 4.9-25.5; p = 0.0037), respectively. For the 11 studies reporting a 100% prior-ASCT rate (n = 662 excluding the brentuximab vedotin trial), the mOS was 28.1 months (95% CI 23.9-34.5), and the difference in mOS between brentuximab vedotin, chemotherapy, allo-SCT, and other therapies was 19.0 (95% CI 12.9-25.1; p < 0.0001), 9.4 (p > 0.05), and 6.8 months (95% CI 1.2-12.5; p = 0.0018), respectively. CONCLUSIONS: While some selection bias may occur when comparing trials with heterogeneous eligibility criteria, in the absence of randomized controlled trial data these results suggest brentuximab vedotin improves long-term survival and is associated with longer mOS in R/R HL post-ASCT compared with other therapies.

Real-world patterns of endocrine therapy for metastatic hormone-receptor-positive (HR+)/human epidermal growth factor receptor-2-negative (HER2-) breast cancer patients in the United States: 2002-2012.

OBJECTIVE: Clinical guidelines recommend that patients with HR+/HER2- metastatic breast cancer (mBC), the most prevalent mBC subtype, receive three lines of endocrine therapy (ET) prior to transitioning to chemotherapy (CT) in the absence of need for rapid response, symptomatic visceral disease, or suspected endocrine resistance. Little is known about real-world ET treatment patterns among HR+/HER2- mBC patients. RESEARCH DESIGN AND METHODS: Post-menopausal women with HR+/HER2- mBC were identified in the MarketScan databases (2002Q3-2012Q2). Patients were classified as receiving either ET or CT as their first therapy post-mBC diagnosis. Those receiving ET were studied further and stratified into three subgroups based on which of the following events occurred first: transition to CT, discontinuation of ET (90 days without evidence of ET), or end of data or insurance eligibility. MAIN OUTCOME MEASURES: Mean numbers of lines of ET and median durations of each line were summarized for the overall sample and subgroups. RESULTS: Among a total of 19,120 HR+/HER2- mBC patients, 11,545 (60%) initiated an ET; median follow-up time for these patients was 17 months. Seventy-four percent did not receive a second ET. The average patient received 1.36 lines of ET. Among patients with 2+ lines of ET, the duration of each subsequent line was significantly shorter than the previous line. RESULTS were similar in all subgroups. LIMITATIONS: Clinical characteristics and reasons for treatment choices are unavailable in claims data. CONCLUSIONS: Fewer than two thirds of patients initiated treatment for HR+/HER2- mBC with ET. Among those who did, most received only one line of ET before discontinuation or transition to CT. Patients who received multiple lines of ET experienced shorter durations of therapy with each line. Real-world treatment with ET falls short of the targets recommended by guidelines, representing unmet need for treatment options that improve the effectiveness of endocrine therapy.