Many drugs increase the risk of cardiovascular disease, such as thiazolidine diketone: rosiglitazone, selective cyclooxygenase (COX)-2 inhibitors: rofecoxib, celecoxib. This study was aimed to find out whether unification of two drugs would increase cardiovascular side effects. Type 2 diabetic rat model was induced through feeding with fodder containing high sugar and lipid and intraperitoneal injection of streptozotocin. The adjuvant-induced arthritis model was established by Paraffin/BCG. We used western blot to explore the protein expression levels of COX-2 and cytochrome P450 (CYP) 4A1. The expression of CYP4A1 was detected by immunohistochemistry. Enzyme-linked immunosorbent assay (Elisa) was used to detect the prostaglandin E2 (PGE-2), 20-Hydroxyeicosatetraenoic acid (20-HETE), endothelin 1 (ET-1) and B-type natriuretic peptide (BNP) in blood serum of diabetes complicating arthritis rats. Blood pressure was measured by a noninvasive caudal artery blood pressure meter. Western blot analysis showed that unification of two drugs caused protein expression levels of COX-2 to reduce obviously and increased protein expression levels of CYP4A1. Immunohistochemistry showed the increased expression of CYP4A1. Elisa indicated that the decreased production of PGE-2 and the increased production of 20-HETE, ET-1 and BNP in blood serum. The blood pressure of rats was increased. The results indicated that unification of two drugs could induce CYP4A1 and inhibit COX-2, and increased production of 20-HETE from arachidonic acid (AA) metabolism. The increased 20-HETE led to the hypertension which could increase markers (ET-1 and BNP) of cardiovascular disease in diabetes complicating arthritis rats. The results showed that the combination of the two drugs could increase the cardiovascular side effects, mainly through the arachidonic acid metabolic pathway CYP450.