The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no Food and Drug Administration (FDA)-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 y of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven in part by accumulation of Alu RNAs, which are noncoding transcripts of a human retrotransposon. Alu RNA induces RPE degeneration by activating the NLRP3-ASC inflammasome. We report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of the NLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other antidepressant drugs, reduces Alu RNA–induced RPE degeneration in mice. Finally, by analyzing two health insurance databases comprising more than 100 million Americans, we report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies identify fluoxetine as a potential drug-repurposing candidate for dry AMD. Significance Dry age-related macular degeneration (AMD) affects the vision of millions of people worldwide. There is currently no Food and Drug Administration–approved treatment for dry AMD. The inflammasome components NLRP3 and ASC have been implicated in the pathogenesis of dry AMD. We report that fluoxetine, which is approved for the treatment of clinical depression, directly binds the NLRP3 protein and prevents NLRP3-ASC inflammasome assembly and activation. Fluoxetine prevents the degeneration of retinal pigmented epithelium cells in an animal model of dry AMD. We also present evidence from a big data analysis of health insurance databases that fluoxetine use is associated with reduced risk of developing dry AMD. These studies identify a potential repurposing candidate for a prevalent cause of blindness.

INTRODUCTION: Inflammasome activation is implicated in Alzheimer's disease (AD). We previously demonstrated that nucleoside reverse transcriptase inhibitors (NRTIs), drugs approved to treat human immunodeficiency virus (HIV) and hepatitis B, also inhibit inflammasome activation.METHODS: We evaluated the association between NRTI exposure and subsequent development of AD in the United States Veterans Health Administration over a 24‐year period and in the MarketScan database over a 14‐year period using propensity score‐matched multivariate Cox hazards regression and Kaplan–Meier analyses.RESULTS: We report that in humans, NRTI exposure was associated with a significantly lower incidence of AD in two of the largest health insurance databases in the United States. In contrast, exposure to non‐NRTIs, protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs) was not associated with reducing AD incidence.DISCUSSION: These findings support the concept that inflammasome inhibition could benefit AD and provide a rationale for prospective clinical testing of inflammasome inhibitors such as NRTIs in AD.Highlights: Exposure to NRTIs, a class of anti‐retroviral drugs that also block inflammasome activation, was associated with a reduction in the risk of developing AD. The reduction in risk was observed in two large, diverse health insurance databases after correcting for numerous comorbidities known to be associated with AD. Other anti‐HIV therapies such as non‐NRTIs, protease inhibitors, and integrase strand transferase inhibitors were not associated with a reduction in the risk of developing AD. Our work provides a rationale for randomized clinical trials of inflammasome inhibitors in AD.

Oral factor Xa (FXa) inhibitors significantly reduce incidence of stroke and thromboembolic events in patients with atrial fibrillation or venous thromboembolism. Due to various factors and the lack of a randomized controlled trial comparing andexanet alfa to usual care, non-specific replacement agents including 4 F-PCC are still used off-label for FXa inhibitor bleed management. Clinical and mortality data were extracted from the inpatient medical data and Veteran Affairs (VA) vital status files over the time of March 2014 through December 2020. Propensity score-weighted models were used for this retrospective cohort study using data from the Veterans Affairs Informatics and Computing Infrastructure (VINCI). The study included 255 patients (85-andexanet alfa and 170-4 F-PCC) exposed to an oral factor Xa inhibitor and hospitalized with an acute major, gastrointestinal (GI), intracranial (ICH) or other bleed. In-hospital mortality was significantly lower in the andexanet alfa cohort compared to the 4 F-PCC cohort (10.6% vs. 25.3%, p = 0.01). Propensity score–weighted Cox models reveal a 69% lower hazard of in-hospital mortality for those treated with andexanet alfa (HR 0.31, 95% CI 0.14–0.71) compared to those treated with 4 F-PCC. Additionally, those treated with andexanet alfa had a lower 30-day mortality rate and lower 30-day hazard of mortality in the weighted Cox model (20.0% vs. 32.4%, p = 0.039; HR 0.54, 95% CI 0.30–0.98) compared to those treated with 4 F-PCC. Among 255 US veterans with major bleeding in the presence of an oral factor Xa inhibitor, treatment with andexanet alfa was associated with lower in-hospital and 30-day mortality than treatment with 4 F-PCC.

Background: Obesity is a risk factor for the development of influenza by leading to a chronic inflammatory state and T-cell dysfunction. Based upon preclinical research, metformin has influenza activity by restoring T-cell function and improving the immune response. Objective: We aimed to evaluate the potential drug repurposing of metformin for the management of influenza among patients with obesity utilizing national claims data in an electronic health record database. Methods: The VA Informatics and Computing Infrastructure (VINCI) was utilized to obtain individual-level information on demographics, administrative claims, and pharmacy dispensation. A cohort was created among individuals with laboratory confirmed diagnosis of influenza with a diagnosis of fever, cough, influenza, or acute upper respiratory infection in an outpatient setting. The study outcome was death after diagnosis of influenza. Cohorts were formed using diabetes status and metformin exposure prior to a positive influenza diagnosis. Hazard ratios for mortality were estimated using a cox proportional hazards model adjusting for baseline covariates and a sub-analysis was conducted utilizing propensity score matching. A greedy nearest neighbor algorithm was utilized to match 1 to 1 non-metformin diabetic controls and non-diabetic controls to diabetic patients receiving metformin. Results: A total of 3551 patients met the inclusion criteria and were evaluated in our study. The cohorts consisted of 1461 patients in the non-diabetic cohort, 1597 patients in the diabetic / metformin cohort, and 493 patients in the diabetic no metformin cohort. Compared to non-diabetic patients, diabetic patients with metformin had a lower rate of death (aHR 0.78, 95% CI 0.609–0.999). There was not a statistical difference between the non-diabetic patients and the diabetic patients without metformin (aHR 1.046, 95% CI 0.781–1.400). The propensity score matched cohorts revealed consistent results with the primary analysis. Conclusion: Our results demonstrated patients with obesity and a history of metformin treatment have lower influenza mortality.

We sought to examine the progression from abdominal aortic aneurysm (AAA) diagnosis to surgery and death among diabetics with and without exposure to metformin as well as non-diabetics. We conducted a retrospective cohort study (January 2000 to July 2019) comparing 3 transitions (AAA surgery, death, and death after AAA surgery) among propensity score-matched metformin-exposed and unexposed diabetic veterans and non-diabetic veterans using the VA Informatics and Computing Infrastructure database. We fit an adjusted Cox proportional hazards model with transition-specific effects. There were 43,073 metformin-unexposed diabetics, 24,361 metformin-exposed diabetics and 56,006 non-diabetics. Compared with the non-diabetic cohort, both diabetic cohorts have a lower risk of surgery (no metformin (HR=0.740, 95% CI 0.706 to 0.776); with metformin (HR=0.770, 95% CI 0.730 to 0.813)). However, the non-metformin diabetic cohort has a higher risk of death (HR=1.024, 95% CI 1.004 to 1.045) and death after surgery (HR=1.086, 95% CI 1.013 to 1.165). The metformin-exposed diabetic cohort has a lower risk of death in the first 10 years after AAA diagnosis (HR=0.877, 95% CI 0.855 to 0.899), yet a higher risk of death 10 years after AAA diagnosis (HR=1.177, 95% CI 1.092 to 1.270) compared with non-diabetic cohort. Non-diabetics have the highest rate of AAA surgery compared with both diabetic cohorts. However, diabetics without metformin have the highest risk of death prior to, and after surgery. This research provides novel findings for patients diagnosed with AAA. The use of metformin after both AAA diagnosis and surgery should be further investigated.