Comparison of Methods to Generalize Randomized Clinical Trial Results Without Individual-Level Data for the Target Population.

Our study explored the application of methods to generalize randomized controlled trial results to a target population without individual-level data. We compared 4 methods using aggregate data for the target population to generalize results from the international trial, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), to a target population of trial-eligible patients in the UK Clinical Practice Research Datalink (CPRD). The gold-standard method used individual data from both the trial and CPRD to predict probabilities of being sampled in the trial and to reweight trial participants to reflect CPRD patient characteristics. Methods 1 and 2 used weighting methods based on simulated individual data or the method of moments, respectively. Method 3 weighted the trial's subgroup-specific treatment effects to match the distribution of an effect modifier in CPRD. Method 4 calculated the expected absolute benefits in CPRD assuming homogeneous relative treatment effect. Methods based on aggregate data for the target population generally yielded results between the trial and gold-standard estimates. Methods 1 and 2 yielded estimates closest to the gold-standard estimates when continuous effect modifiers were represented as categorical variables. Although individual data or data on joint distributions remains the best approach to generalize trial results, these methods using aggregate data might be useful tools for timely assessment of randomized trial generalizability.

Generalizing Randomized Clinical Trial Results: Implementation and Challenges Related to Missing Data in the Target Population.

Statins are indicated in patients with elevated levels of high-sensitivity C-reactive protein and normal low-density lipoprotein cholesterol based on results of the multicountry trial, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) (2003-2008), but the benefit in real-world populations remains unknown. We sought to generalize JUPITER results to trial-eligible population using data from the UK Clinical Practice Research Datalink (CPRD), 2001-2014. We multiply imputed missing baseline characteristics for the CPRD population and selected the trial-eligible participants as the target population based on observed and imputed values. Trial participants were weighted to be representative of the CPRD population (n = 383,418) based on individual predicted probability of selection into the trial. Trial participants were also standardized to the CPRD population without missing values (n = 2,677). In JUPITER, rosuvastatin reduced cardiovascular risk with a 3-year risk difference of -2.0% (95% confidence interval (CI): -2.9, -1.1). The rosuvastatin effect was muted in the first 2 years but remained strong at 3 years after standardizing to the imputed CPRD population (3-year risk difference = -2.7%; 95% CI: -5.8, 0.4) and the CPRD population without missing data (3-year risk difference = -1.7%; 95% CI: -3.5, 0.1). The study serves as an illustration of possible approaches to understanding generalizability of trials using real-world databases given limitations due to missing data on inclusion/exclusion criteria.

Comparative Effect of Initiating Metformin Versus Sulfonylureas on Breast Cancer Risk in Older Women.

BACKGROUND: Several observational studies have reported that metformin may be associated with reduced risk of breast cancer; however, many of these studies were affected by time-related biases such as immortal time bias and time-window bias. This study aimed to examine the relative risk of breast cancer for older women initiating metformin versus sulfonylureas while avoiding such biases. METHODS: The study cohort consisted of women aged 65+ who initiated monotherapy with metformin (n = 45,900) or sulfonylureas (n = 13,904) and were free of cancer and renal disease within 6 months before treatment initiation using 2007-2012 US Medicare claims data. We followed treatment initiators for incident breast cancer, and estimated hazard ratios using weighted Cox models. Unmeasured confounding by body mass index and smoking was further adjusted by propensity score calibration using external information from Medicare Current Beneficiary Survey 2006-2009 panels. RESULTS: During 58,835 and 16,366 person-years of follow-up, 385 initiators of metformin treatment and 95 of sulfonylurea were diagnosed with breast cancer. Metformin initiators did not have a reduced risk of breast cancer compared with sulfonylurea initiators (hazard ratio: 1.2; 95% confidence interval: 0.94, 1.6). Externally controlling for body mass index and smoking did not affect the estimates. CONCLUSION: The findings of this study provide no support for a reduced risk of breast cancer after initiation of metformin compared with a clinical alternative in older women. This study is limited by the relatively short follow-up time and we cannot exclude the possible benefits of long-time metformin use on breast cancer risk.

Differential Use of Screening Mammography in Older Women Initiating Metformin versus Sulfonylurea.

PURPOSE: Differential use of screening mammography may lead to biased detection of breast cancer. This study aimed to compare receipt of screening mammography and the incidence of screen-detected breast cancer between metformin and sulfonylurea initiators. METHODS: We used 2006-2014 US Medicare claims to identify initiators of metformin or sulfonylurea aged 65+ years continuously enrolled in Parts A/B for ≥2 years pre-initiation and ≥2 years post-initiation. We reported frequencies of screening mammograms and screen-detected breast cancer in 1 year pre-initiation among all cohort members and in 1 year post-initiation among cancer-free cohort members. Weighted screening risk differences (RDs) were estimated comparing metformin to sulfonylurea group. RESULTS: We identified 41,436 and 13,367 initiators of metformin and sulfonylurea, 35% and 24% of which had ≥1 screening mammogram in 1 year pre-initiation (weighted RD: 6 percentage points; 95% CI: 5 to 7), respectively. The weighted RD for screen-detected breast cancer associated with metformin was 0.00 percentage points (95% CI: -0.09 to 0.09). Among cancer-free cohort members, metformin initiators had 5 percentage points (95% CI: 4 to 6) and 0.11 percentage points (95% CI: -0.02 to 0.23) absolute risk excess of screening mammography and screen-detected breast cancer in 1 year post-initiation, compared with sulfonylurea initiators, respectively. CONCLUSIONS: Metformin initiators were more likely to receive screening mammograms than sulfonylurea initiators pre- and post-initiation, indicating possible detection bias due to differential screening mammography. Researchers should be aware of the potential for more screening mammograms pre- and post-initiation when interpreting the findings of metformin on breast cancer incidence. Copyright © 2017 John Wiley & Sons, Ltd.

Identification of impaired fasting glucose, healthcare utilization and progression to diabetes in the UK using the Clinical Practice Research Datalink (CPRD).

PURPOSE: Few studies have examined patients with prediabetes in usual, "real-world" clinical practice settings. Among patients with impaired fasting glucose (IFG), we aimed to describe the rates of progression to diabetes and to examine the long-term reduction in diabetes risk associated with regression to normoglycemia at 1 year. METHODS: The UK-based study included 120 055 non-diabetic patients in Clinical Practice Research Datalink from 2001 to 2012 aged 25+ years and with ≥1 fasting plasma glucose (FPG) test between ≥6.1 and <7.0 mmol/l indicating IFG who were followed for progression to diabetes. In a subgroup of 45 167 patients with IFG with subsequent FPG results 1 year later, we assessed the 1-year glycemic status change and estimated the relative hazard of diabetes comparing patients with regression to normoglycemia (IFG-normoglycemia) to those who remained in IFG (IFG-IFG) using a multivariable Cox model. RESULTS: Among patients with IFG with over 414 649 person-years of follow-up, 52% received a subsequent FPG test, and 10% developed diabetes within 1 year after recognition of IFG. The incidence rate of diabetes was 5.86 (95% CI: 5.78 to 5.93) per 100 person-years. In the subgroup analysis, 31% of these patients remained in IFG, while 53% and 16% converted to normoglycemia or diabetes, respectively. The adjusted hazard ratio of developing diabetes was 0.33 (95% CI: 0.31 to 0.35) comparing IFG-normoglycemia to IFG-IFG. CONCLUSIONS: IFG is a high-risk state for diabetes. Regression to normoglycemia from IFG strongly reduces the long-term risk of developing diabetes. Our study also shows the feasibility of identifying patients with IFG in the Clinical Practice Research Datalink. Copyright © 2016 John Wiley & Sons, Ltd.

Metformin and the risk of endometrial cancer: a population-based cohort study.

OBJECTIVE: While some observational studies have suggested a protective effect of metformin on incident cancer, concerns about potential bias remain. We compared the incidence of endometrial cancer in metformin versus sulfonylurea initiators. Research design and methods We conducted a retrospective cohort analysis using US healthcare claims (MarketScan®), 2000-2011. We identified new users of metformin versus sulfonylureas with no prior cancer diagnoses and followed them until a diagnosis of endometrial cancer, hysterectomy, treatment change, or disenrollment. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards, using an as-treated analytic approach. Stabilized inverse probability of treatment weights were used to adjust for potential confounding at baseline. RESULTS: Of 541,128 eligible women, 456,838 (84%) initiated metformin and 84,290 (16%) initiated sulfonylurea. The treatment groups differed at baseline in terms of age and recent diagnosis codes for diabetes, polycystic ovarian syndrome, and endometrial hyperplasia. Over a median follow-up of 1.2 (IQR 0.4-2.3) years and a total of 2,030,914 person-years, 729 women developed endometrial cancer. Metformin initiation was associated with a lower risk of endometrial cancer in the unadjusted analysis (HR 0.81, 95% CI 0.67-0.97). However, after balancing baseline covariates across groups, metformin was not associated with a reduced risk of endometrial cancer (HR 1.09, 95% CI 0.88-1.35). This finding was consistent across multiple sensitivity analyses and subgroup analyses in diabetic patients and relevant age groups. CONCLUSIONS: In this population-based cohort of >500,000 women, initiating metformin compared with sulfonylureas was not associated with a reduced risk of developing endometrial cancer.

Efficacy of Mobocertinib and Amivantamab in Patients With Advanced Non-Small Cell Lung Cancer With EGFR Exon 20 Insertions Previously Treated With Platinum-Based Chemotherapy: An Indirect Treatment Comparison.

INTRODUCTION: Exon 20 insertions (ex20ins) mutations of the EGFR gene account for 1% to 2% of all non-small-cell lung cancers (NSCLCs). Targeted therapies have been developed to treat this cancer type but have not been studied in head-to-head trials. Our objective was to use a matching-adjusted indirect comparison (MAIC) to assess the efficacy of mobocertinib and amivantamab in patients with NSCLC EGFR ex20ins mutations who were previously treated with platinum-based chemotherapy. MATERIALS AND METHODS: An unanchored MAIC was conducted to estimate the treatment effects of mobocertinib and amivantamab using individual-level data from the mobocertinib phase I/II single-arm trial (NCT02716116) and published data from the amivantamab single-arm CHRYSALIS trial (NCT02609776). Confirmed overall response rate (cORR), progression-free survival (PFS), overall survival (OS), and duration of response (DoR) were assessed. RESULTS: Both trials were comparable in terms of study population, study design, and outcome definitions and included 114 patients who received mobocertinib and 114 patients who received amivantamab. After MAIC weighting, all reported baseline characteristics were balanced between mobocertinib and amivantamab. The weighted odds ratio (OR) [95% confidence interval (CI)] comparing mobocertinib to amivantamab was 0.56 (0.30-1.04) for independent review committee (IRC)-assessed cORR and 0.98 (0.53-1.82) for investigator (INV)-assessed cORR. The weighted hazard ratio (HR) comparing mobocertinib to amivantamab was 0.74 (0.51-1.07) for IRC-assessed PFS, 0.92 (0.57-1.48) for OS, and 0.59 (0.30-1.18) for INV-assessed DoR. CONCLUSION: MAIC analysis showed that mobocertinib and amivantamab had similar efficacy in patients with NSCLC harboring EGFR ex20ins mutations whose disease progressed during or after platinum-based chemotherapy. These findings may benefit patients by supporting future treatment options.

Epidemiology, Disease Course, and Clinical Outcomes of Perianal Fistulas and Fissures Crohn's Disease: A Nationwide Population-Based Study in Taiwan.

Background: Population-based data on the course of perianal disease in East Asian populations with Crohn's disease (CD) are limited. This study examined the prevalence, clinical course, and compared the outcomes of CD patients with perianal CD (pCD) versus without pCD in Taiwan. Methods: A nationwide population-based study was implemented from 2000 to 2017 by using the Taiwan National Health Insurance Research Database. Results: Of 2424 patients with CD, 358 (14.8%) patients with pCD were identified. Most patients with CD and pCD were men (79.3%). The mean age at CD diagnosis was lower in patients with pCD (33.7 years) than in those without pCD (44.9 years). Approximately half the patients with pCD received the pCD diagnosis at least 6 months before receiving a CD diagnosis. Approximately one-third (121/358) of patients with pCD had recurrent fistula; the median recurrence interval was 239 days. Compared with patients without pCD, patients with pCD had higher mean incidences of hospitalization (7.0 vs 3.8, P < .01), outpatient visits (13 vs 2.9, P < .01), and emergency room visits (10.3 vs 4.4, P < .01) over a 15-year period. Although patients with pCD had higher rates of healthcare utilization, their 15-year mortality rate was lower than that of those without pCD (6.1% vs 17.3%, P < .01). Conclusions: The period prevalence of pCD in Taiwanese patients with CD was 14.8%. Although patients with pCD required more intensive care and had greater healthcare utilization, they did not have inferior survival outcomes compared with those without pCD.

Real-World Response and Outcomes in Patients With NSCLC With EGFR Exon 20 Insertion Mutations.

Introduction: This study describes treatment patterns and outcomes in patients with NSCLC with EGFR exon 20 insertions (EGFRex20ins) in the United States. Methods: The Flatiron Health electronic health record database was used to select three cohorts among patients diagnosed with NSCLC with EGFRex20ins (January 1, 2011-February 29, 2020): (1) first-line (1L) or patients receiving 1L therapy after documented EGFRex20ins; (2) second or later-line (≥2L) or patients receiving ≥2L therapy after documented EGFRex20ins; and (3) ≥2L postplatinum trial-aligned, or ≥2L patients previously treated with platinum chemotherapy whose baseline characteristics aligned with key eligibility criteria (initiating new treatment after documented EGFRex20ins and ≥1 previous treatment excluding mobocertinib or amivantamab) of the mobocertinib trial NCT02716116. Real-world end points were confirmed overall response rate, overall survival, and progression-free survival. Results: Of 237 patients with EGFRex20ins-mutated NSCLC, 129 and 114 patients were included in the 1L and ≥2L cohorts, respectively. In 1L patients, platinum chemotherapy plus nonplatinum chemotherapy (31.0%) and EGFR tyrosine kinase inhibitors (28.7%) were the most common regimens. In ≥2L patients, immuno-oncology monotherapy (28.1%) and EGFR tyrosine kinase inhibitors (17.5%) were the most common index treatments. For any 1L, ≥2L, and ≥2L postplatinum trial-aligned patients, the confirmed overall response rate was 18.6%, 9.6%, and 14.0%, respectively; the median overall survival was 17.0, 13.6, and 11.5 months; the median progression-free survival was 5.2, 3.7, and 3.3 months, respectively. Conclusions: The outcomes for patients with NSCLC with EGFRex20ins were poor. This real-world study provides a benchmark on treatment outcomes in this patient population and highlights the unmet need for improved therapeutic options.

Distribution and Detectability of EGFR Exon 20 Insertion Variants in NSCLC.

INTRODUCTION: EGFR exon 20 insertion (ex20ins) mutations represent 5% to 10% of EGFR mutations in NSCLC. Identifying patients with EGFR ex20ins is challenging owing to the limited coverage of polymerase chain reaction (PCR) assays and the relatively recent use of next-generation sequencing (NGS). This study analyzes the spectrum of EGFR ex20ins variants in a large patient population from a global clinical trial and several real-world cohorts and the ability of PCR kits to identify these alterations. METHODS: We conducted this retrospective analysis in patients with NSCLC who underwent NGS or other sequencing testing and had a known EGFR ex20ins mutation. Patients were gathered from a clinical trial (NCT02716116), a chart review study in Germany, and the LC-SCRUM-Japan, GENIE, and U.S. COTA databases. Proportions of patients with ex20ins variants that could have been detected by six commercially available and widely used PCR kits were calculated in each data set. RESULTS: Overall, 636 patients with NSCLC harboring EGFR ex20ins mutations were included in this analysis and 104 unique EGFR ex20ins variants were identified across the data sources. The proportion of patients whose ex20ins could have been detected by any PCR test alone ranged from 11.8% to 58.9% across the data sources. CONCLUSIONS: Our findings suggest that the PCR tests evaluated would have missed more than 40% of patients with NSCLC harboring EGFR ex20ins mutations. NGS-based genetic testing is preferable than standard PCR assays and can substantially improve the identification of the diverse profile of EGFR ex20ins variants in NSCLC.

Comparative effectiveness of mobocertinib and standard of care in patients with NSCLC with EGFR exon 20 insertion mutations: An indirect comparison.

INTRODUCTION: Mobocertinib is a novel, first-in-class, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to selectively target in-frame EGFR exon 20 insertions (ex20ins). Comparative effectiveness data for mobocertinib versus real-world treatments are lacking in this rare population. This study compared data for mobocertinib reported in a Phase I/II single-arm clinical trial with an external control group consisting of patients who received available treatment in the real-world setting in the United States (US). MATERIALS AND METHODS: The mobocertinib group included platinum-pretreated patients with advanced EGFR ex20ins non-small cell lung cancer (NSCLC) receiving mobocertinib 160 mg QD in an ongoing, single-arm, phase 1/2 clinical trial (NCT02716116; n = 114). The real-world data (RWD) group included platinum-pretreated patients with advanced EGFR ex20ins-mutant NSCLC from the Flatiron Health database (n = 50). Inverse probability treatment weighting based on the propensity score method controlled for potential confounding between groups. Confirmed overall response rate (cORR), progression-free survival (PFS), and overall survival (OS) were compared between groups. RESULTS: After weighting, baseline characteristics were balanced. Patients in the RWD group received EGFR TKI (20 %), immuno-oncology therapy (40 %), or any regimens containing chemotherapy (40 %) in the second- or later-line setting. In the mobocertinib and RWD groups, respectively, cORR was 35.1 % and 11.9 % (odds ratio: 3.75 [95 % confidence interval (CI): 2.05, 6.89]); median PFS was 7.3 and 3.3 months (hazard ratio [HR]: 0.57 [95 % CI: 0.36, 0.90]); and median OS was 24.0 and 12.4 months (HR: 0.53 [95 % CI: 0.33, 0.83]) after weighting. DISCUSSION: Mobocertinib showed substantially improved outcomes versus an external control group using available therapies in platinum-pretreated patients with EGFR ex20ins-mutant NSCLC. In the absence of comparative evidence from randomized trials, these findings help elucidate potential benefits of mobocertinib in this rare population.

Indirect comparison of mobocertinib and real-world therapies for pre-treated non-small cell lung cancer with EGFR exon 20 insertion mutations.

OBJECTIVES: Mobocertinib, a novel oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is available for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) mutations after platinum chemotherapy. We performed an indirect comparison of clinical trial data and real-world data (RWD) to determine the relative efficacy of mobocertinib vs. other treatments for these patients. MATERIALS AND METHODS: Data on the efficacy of mobocertinib from a phase I/II trial (NCT02716116) were compared to RWD from a retrospective study in 12 German centers using inverse probability of treatment weighting to adjust for age, sex, Eastern Cooperative Oncology Group score, smoking status, presence of brain metastasis, time from advanced diagnosis, and histology. Tumor response assessment was based on RECIST v1.1. RESULTS: The analysis included 114 patients in the mobocertinib group and 43 in the RWD group. The confirmed overall response rate (cORR) according to investigator assessment was 0% for standard treatments and 35.1% (95% confidence interval [CI], 26.4-44.6) for mobocertinib (p < 0.0001). Compared to standard regimens in the weighted population, mobocertinib prolonged overall survival (OS, median [95% CI] = 9.8 [4.3-13.7] vs. 20.2 [14.9-25.3] months; hazard ratio [HR] = 0.42 [0.25-0.69], p = 0.0035), progression-free survival (PFS, median [95% CI] = 2.6 [1.5-5.7] vs. 7.3 [5.6-8.8] months; HR = 0.28 [0.18-0.44], p < 0.0001), and time to treatment discontinuation (median [95% CI] = 2.1 [1.2-3.1] vs. 7.4 [6.4-8.5] months; HR = 0.34 [0.18-0.65], p = 0.0004). CONCLUSION: Mobocertinib was associated with an improved cORR and prolonged PFS and OS compared to standard treatments for patients with EGFR ex20ins-positive NSCLC previously treated with platinum-based chemotherapy.

The impact of TP53 co-mutations and immunologic microenvironment on outcome of lung cancer with EGFR exon 20 insertions.

BACKGROUND: EGFR exon20 insertions (ex20ins) are targeted by novel compounds in non-small-cell lung cancer (NSCLC). However, data about outcome under conventional therapies and the influence of molecular features are scarce. PATIENTS AND METHODS: We retrospectively analysed 118 patients with evaluation of radiologic response based on RECIST v1.1. TP53 status was available for 88 cases. RESULTS: Platinum doublets and chemoimmunotherapy showed similar response rates (20-25%), disease control rates (80%) and median progression-free survival (mPFS, ≈7 months), which were longer compared to monochemotherapy (9%, 59%, 4.1 months), EGFR inhibitors (0%, 46%, 3.0) and PD-(L)1 inhibitors (0%, 30%, 2.1; p < 0.05). Overall survival (OS) was not dependent on the choice of first-line treatment, but related to more lines of systemic therapy (p < 0.05). TP53 mutations and brain metastases were associated with shorter PFS under platinum doublets and EGFR inhibitors (HR 3.3-6.1, p < 0.01), and shorter OS for patients receiving both treatments (p < 0.05). More tumour CD8+ and less Th1 cells were associated with longer OS independent of brain and TP53 status (p < 0.01). No difference in outcome was noted according to the ex20ins site and use of pemetrexed (vs. other cytotoxics) or bevacizumab. Long-lasting responses (>1 year) occasionally occurred under EGFR inhibitors for both 'near-' and 'far-loop' variants. CONCLUSIONS: Platinum doublets and chemoimmunotherapy have the highest activity with ORR of 20-25% and mPFS of approximately 7 months, regardless of the cytotoxic partner, while PD-(L)1 inhibitors show limited efficacy. TP53 mutations, brain metastases and a lower tumour CD8/Th1-cell ratio are independently associated with shorter survival.

Pharmacokinetics of dietary cancer chemopreventive compound dibenzoylmethane in rats and the impact of nanoemulsion and genetic knockout of Nrf2 on its disposition.

The pharmacokinetic disposition of a dietary cancer chemopreventive compound dibenzoylmethane (DBM) was studied in male Sprague-Dawley rats after intravenous (i.v.) and oral (p.o.) administrations. Following a single i.v. bolus dose, the mean plasma clearance (CL) of DBM was low compared with the hepatic blood flow. DBM displayed a high volume of distribution (Vss). The elimination terminal t1/2 was long. The mean CL, Vss and AUC0-∞/dose were similar between the i.v. 10 and 10 mg/kg doses. After single oral doses (10, 50 and 250 mg/kg), the absolute oral bioavailability (F*) of DBM was 7.4%-13.6%. The increase in AUC was not proportional to the oral doses, suggesting non-linearity. In silico prediction of oral absorption also demonstrated low DBM absorption in vivo. An oil-in-water nanoemulsion containing DBM was formulated to potentially overcome the low F* due to poor water solubility of DBM, with enhanced oral absorption. Finally, to examine the role of Nrf2 on the pharmacokinetics of DBM, since DBM activates the Nrf2-dependent detoxification pathways, Nrf2 wild-type (+/+) mice and Nrf2 knockout (-/-) mice were utilized. There was an increased systemic plasma exposure of DBM in Nrf2 (-/-) mice, suggesting that the Nrf2 genotype could also play a role in the pharmacokinetic disposition of DBM. Taken together, the results show that DBM has low oral bioavailability which could be due in part to poor water solubility and this could be overcome by a nanotechnology-based drug delivery system and furthermore the Nrf2 genotype could also play a role in the pharmacokinetics of DBM.

Adherence to Statins Use and Risk of Dementia among Patients with Diabetes and Comorbid Hyperlipidemia.

The results from previous observational studies and clinical trials about the neuroprotective benefits of statins use for the prevention of dementia are contradictory. It is unclear whether the neuroprotective benefits are experienced in a specific group with a higher risk of dementia, such as patients with concurrent diabetes and hyperlipidemia. We aimed to examine the association between adherence to statins and the risk of dementia among patients with diabetes and comorbid hyperlipidemia. This was a retrospective study with a new user design. We used data from the Taiwan National Health Insurance Research Database to identify patients with diabetes and comorbid hyperlipidemia. The occurrence of dementia was the study outcome. The adherence to statins was the exposure, which was measured by the proportion of days covered (PDC) of statins. The good adherence included patients with ≥80% PDC of statins. Cox proportional hazards regression models were used to evaluate the association between adherence to statins and dementia. Among 18,125 included individuals with diabetes and comorbid hyperlipidemia, 33.5% had good adherence to statins. Compared to poor adherence to statins, good adherence to statins was not significantly associated with a reduced risk of dementia (hazard ratio = 0.94; 95%confidence interval = 0.70-1.24) among patients with diabetes and comorbid hyperlipidemia. Good adherence to statins was not found to be associated with the risk of dementia among patients with diabetes and comorbid hyperlipidemia in Taiwan. Future studies with a more diverse study population are needed to evaluate the neuroprotective effects of statins use on dementia prevention.

The Risk of Acute Pancreatitis After Initiation of Dipeptidyl Peptidase 4 Inhibitors: Testing a Hypothesis of Subgroup Differences in Older U.S. Adults.

OBJECTIVE: To examine whether dipeptidyl peptidase 4 inhibitors (DPP-4I) increase acute pancreatitis risk in older patients and whether the association varies by age, sex, and history of cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: We conducted a cohort study of DPP-4I initiators versus thiazolidinedione (TZD) or sulfonylurea initiators using U.S. Medicare beneficiaries, 2007-2014. Eligible initiators were aged 66 years or older without history of pancreatic disease or alcohol-related diseases. Patients were followed up for hospitalization due to acute pancreatitis and censored at 90 days after treatment changes. Weighted Cox models were used to estimate the hazard ratio (HR) for acute pancreatitis. Analyses were performed overall as well as within subgroups defined by age, sex, and CVD history. RESULTS: We found no increased risk of acute pancreatitis comparing 49,374 DPP-4I initiators to 132,223 sulfonylurea initiators (weighted HR 1.01; 95% CI 0.83-1.24) and comparing 57,301 DPP-4I initiators to 32,612 TZD initiators (weighted HR 1.11; 95% CI 0.76-1.62). Age and sex did not modify the association. Among patients with CVD, acute pancreatitis incidence was elevated in initiators of DPP-4I and sulfonylurea (2.3 and 2.4 per 1,000 person-years, respectively) but not in TZD initiators (1.5). Among patients with CVD, higher risk of acute pancreatitis was observed with DPP-4I compared with TZD (weighted HR 1.84; 95% CI 1.02-3.35) but not compared with sulfonylurea. CONCLUSIONS: Our study provides evidence that DPP-4I is not associated with an increased risk of acute pancreatitis in older adults overall. The positive association observed in patients with CVD could be due to chance or bias but merits further investigation.

Incretin-Based Therapies and Diabetic Retinopathy: Real-World Evidence in Older U.S. Adults.

OBJECTIVE: Recent large trials yield conflicting results on the association between incretin-based therapies (IBTs) and diabetic retinopathy (DR). We examined whether IBTs increase DR risk compared with other antihyperglycemics. RESEARCH DESIGN AND METHODS: We implemented an active comparator, new-user cohort design using a nationwide 20% random sample of fee-for-service U.S. Medicare beneficiaries aged 65 years or older with Parts A, B, and D coverage between 2007 and 2015. We identified the following cohorts without prior treatment for retinopathy: dipeptidyl peptidase 4 inhibitors (DPP4i) versus sulfonylureas (SU), DPP4i versus thiazolidinediones (TZD), glucagon-like peptide-1 receptor agonists (GLP1RA) versus long-acting insulin (LAI), and GLP1RA versus TZD. Primary outcome was advanced diabetic retinopathy requiring treatment (ADRRT), defined as a procedure code for retinopathy treatment. Incident diabetic retinopathy (IDR), identified by a diagnosis code, was a secondary outcome. We estimated propensity scores to balance confounders and adjusted hazard ratios (95% CI) using weighted Cox proportional hazards models. RESULTS: We identified 213,652 eligible patients. During a median duration of 0.58 to 0.87 years across comparisons, with a rate from 6.0 to 12.8 per 1,000 person-years, IBTs were not associated with increased ADRRT or IDR risk. The adjusted hazard ratios (95% CI) for ADRRT were 0.91 (0.79-1.04) by comparing DPP4i to SU (n = 39,292 and 87,073); 0.91 (0.75-1.11), DPP4i to TZD (n = 51,410 and 22,231); 0.50 (0.39-0.65), GLP1RA to LAI (n = 9,561 and 82,849); and 0.75 (0.53-1.06), GLP1RA to TZD (n = 10,355 and 27,345). CONCLUSIONS: Our population-based cohort study of older U.S. adults with diabetes suggests that IBTs used for approximately 1 year do not increase the DR risk.

Development and validation of an HPLC method for the determination of dibenzoylmethane in rat plasma and its application to the pharmacokinetic study.

A highly sensitive and simple high-performance liquid chromatographic (HPLC) assay has been developed and validated for the quantification of dibenzoylmethane (DBM) in rat plasma. DBM and internal standard (I.S.) 1-(5-chloro-2-hydroxy-4-methylphenyl)-3-phenyl-1,3-propanedione (CHMPP) were extracted from rat plasma by ethyl acetate/methanol (95:5, v/v) and analyzed using reverse-phase gradient elution with a Phenomenex Gemini C18 5-mum column. A gradient of mobile phase (mobile phase A: water/methanol (80:20, v/v) with 0.1% TFA and mobile phase B: acetonitrile with 0.1% TFA) at a flow rate of 0.2 mL/min, and ultraviolet (UV) detection at 335 nm were utilized. The lower limit of quantification (LLOQ) using 50 microL rat plasma was 0.05 microg/mL. The calibration curve was linear over a concentration range of 0.05-20 microg/mL. The mean recoveries were 80.6+/-5.7, 83.4+/-1.6 and 77.1+/-3.4% with quality control (QC) level of 0.05, 1 and 20 microg/mL, respectively. Intra- and inter-day assay accuracy and precision fulfilled US FDA guidance for industry bioanalytical method validation. Stability studies showed that DBM was stable in rat plasma after 4h incubation at room temperature, one month storage at -80 degrees C and three freeze/thaw cycles, as well as in reconstitute buffer for 48 h at 4 degrees C. The utility of the assay was confirmed by the successful analysis of plasma samples from DBM pharmacokinetics studies in the rats after oral and intravenous administrations.

The Association Between the Use of Zolpidem and the Risk of Alzheimer's Disease Among Older People.

OBJECTIVES: To evaluate the association between zolpidem use and the risk of Alzheimer's disease among older people. DESIGN: A retrospective cohort study using data from 2001 to 2011 from the National Health Insurance Research Database. SETTING: Taiwan. PARTICIPANTS: A total of 6,922 patients aged 65 years or older enrolled from January 2002 to December 2004 (the enrollment period). INTERVENTION (EXPOSURE): Zolpidem users were identified as patients who used zolpidem during the enrollment period. The index date was the date of the first zolpidem prescription. Dosage of zolpidem use was defined using cumulative defined daily dose (cDDD) based on the cumulative dosage that patients took within one year after the index date (grouped as: less than 28, 28-90, 91-180, and more than 180 cDDD). MEASUREMENTS: The occurrence of Alzheimer's disease was defined as the time period from the end of one year after the index date to the date of the Alzheimer's disease diagnosis. The propensity score was used to adjust the measured confounders of Alzheimer's disease. Cox proportional hazards models were used to evaluate the association between zolpidem use and the incidence of Alzheimer's disease. RESULTS: Zolpidem users with a high cumulative dose (>180 cDDD) in the first year after initiation had a significantly greater risk of Alzheimer's disease than non-zolpidem users (HR = 2.97, 95% CI = 1.61-5.49) and low cumulative dose (<28 cDDD) users (HR = 4.18, 95% CI = 1.77-9.86). CONCLUSION: We found the use of a high cumulative dose of zolpidem was associated with an increased risk of Alzheimer's disease among older people living in Taiwan. It is advised to use caution when considering long-term use of zolpidem in older patients.