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Background: Pleiotropic effects on cardiovascular protection have been suggested in several oral antidiabetic drugs (OAD). The impacts of OADs on aortic aneurysm (AA) growth have been found in animal studies, but the evidence of their beneficial effects for AA protection in human are lacking. We investigated the relationship between OAD therapy and the risk of developing AA. Methods: We conducted a nested case-control analysis using the database extracted from Taiwan's National Health Insurance Research Database. The database consists of 1.2 million diabetic patients representing the majority of the type 2 diabetes population in Taiwan from 2000 to 2013. Cases were identified as those with either inpatient or outpatient diagnosis code of AA. One control was selected for each case matching on duration of follow-up, age, sex, urbanization, monthly income, severity of diabetes, and risk factor for AA. We identified variable classes of OADs, including metformin, sulfonylureas, thiazolidinedione (TZD), alpha-glucosidase inhibitors, meglitinide, dipeptidyl peptidase-4 (DPP-4) inhibitors prior to the development of AA. Results: A total of 4468 cases diagnosed with AA and 4468 matched controls were identified. Metformin use, sulfonylurea use, and TZD were associated with lower risk of developing AA, odds ratio [OR] 0.72 (95 % confidence interval [CI] 0.64-0.80), 0.82 (95 % CI 0.74-0.92), and 0.82 (95 % CI 0.69-0.98), respectively. The effects of metformin and sulfonylurea on AA were dose responsive. Neither alpha-glucosidase inhibitors (OR 0.95; 95 % CI 0.81-1.11) nor DPP-4 inhibitors (OR 0.85; 95 % CI 0.68-1.07) was significantly associated with AA events. Conclusions: Metformin, sulfonylurea, and TZD treated patients were associated with lower risks of AA development, but not DPP-4 inhibitors or alpha-glucosidase inhibitor. The protective effects of hypoglycemic agents are further confirmed by the dose responsive relations in metformin and sulfonylurea groups. [ABSTRACT FROM AUTHOR]

Background—Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including endothelial nitric oxide synthase–derived nitric oxide bioavailability. Here, we postulated that oxidative stress induces sterol regulatory element–binding protein 2 (SREBP2) and microRNA-92a (miR-92a), which in turn activate endothelial innate immune response, leading to dysfunctional endothelium. Methods and Results—Using cultured endothelial cells challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and angiotensin II–infused or aged mice, we demonstrated that SREBP2 transactivation of microRNA-92a (miR-92a) is oxidative stress inducible. The SREBP2-induced miR-92a targets key molecules in endothelial homeostasis, including sirtuin 1, Krüppel-like factor 2, and Krüppel-like factor 4, leading to NOD-like receptor family pyrin domaincontaining 3 inflammasome activation and endothelial nitric oxide synthase inhibition. In endothelial cell–specific SREBP2 transgenic mice, locked nucleic acid–modified antisense miR-92a attenuates inflammasome, improves vasodilation, and ameliorates angiotensin II–induced and aging-related atherogenesis. In patients with coronary artery disease, the level of circulating miR-92a is inversely correlated with endothelial cell–dependent, flow-mediated vasodilation and is positively correlated with serum level of interleukin-1β. Conclusions—Our findings suggest that SREBP2–miR-92a–inflammasome exacerbates endothelial dysfunction during oxidative stress. Identification of this mechanism may help in the diagnosis or treatment of disorders associated with oxidative stress, innate immune activation, and endothelial dysfunction. [ABSTRACT FROM AUTHOR]