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It is well known that diabetic patients are at higher risk for cardiovascular events such as stroke or myocardial infarction (MI).1 However until 2008, companies seeking approval for new diabetes medications were not required to demonstrate cardiovascular outcomes, either positive or negative. Newer trials for diabetes medications have shown that some agents are effective at lowering blood sugar, but may actually increase the risk of cardiovascular disease (CVD).2 The concerns for the cardiovascular effects became strong enough that the FDA started requiring proof not only of efficacy in glucose-lowering, but also safety with cardiovascular outcomes for antidiabetic medications.3,4 Sulfonylureas and metformin were two medication classes not required to report their cardiovascular outcomes at the time of their approval.3 Therefore, the case of their effects on cardiovascular outcomes had gone cold. Only recently was it reopened, with the retrospective cohort study through the National Veterans Health Administration (VHA) databases.5

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The investigators studied over a period of 7 years a cohort of veterans, ≥18 years old, who filled prescriptions regularly (at least every 180 days), were enrolled at the VHA for at least one year, and were new users of metformin or sulfonylureas (glyburide or glipizide). Patients were excluded if they had any serious medical conditions such as heart failure, cancer, HIV, kidney failure, liver disease, or respiratory failure, cocaine use, or a baseline serum creatinine of ≥1.5 mg/dL. Patients were followed until they had a switch or addition of another antidiabetic medication, or a censoring event (serum creatinine ≥1.5 mg/dL, the 181st day of no contact with any VHA facility, or the end of the study). Primary composite outcome consisted of acute MI, stroke, or death. The secondary outcome was CVD (MI or stroke) alone. Enrolled patients were predominately white (75%), males (97%), and between the ages of 62-67 years. Covariates, used to remove any confounding variables included: age, sex, race, and physiological variables closest to the cohort entry (blood pressure, serum creatinine, A1c, LDL-C, BMI, smoking status, CVD medications, comorbid conditions and indicators of health care utilization).5 

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Among the 253,690 patients (98,665 sulfonylurea vs. 155,025 metformin) the unadjusted rates of the composite outcome were 18.2 per 1000 person-years with sulfonylurea vs. 10.4 per 1000 person-years with metformin (hazard ratio, 1.21 [95% CI, 1.13-1.30]). For the secondary outcome of CV events alone, the unadjusted hazard ratio was 1.16 (95% CI, 1.06-1.25). Using the adjusted results, the researchers estimated that 2.2 (95% CI, 1.4 to 3.0) more CVD events or deaths per 1000 person-years occurred with sulfonylureas compared with metformin. Results did not differ when comparing glyburide and glipizide. The authors concluded that patients in whom diabetes was initially treated with sulfonylureas had a higher occurrence of cardiovascular events than those who used metformin as initial treatment. Therefore, they support the use of metformin as the preferred initial treatment for patients with new onset Type 2 diabetes. Unfortunately, however, the findings do not help to ...

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