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Shosaku Nomura,1 Akira Shouzu,2 Takehito Taniura,3 Yoshinori Okuda,4 Seitaro Omoto,5 Masahiko Suzuki,6 Tomoki Ito,7 Nagaoki Toyoda8 1Center of Thrombosis and Hemostasis, Kansai Medical University Medical Center, Moriguchi, Japan; 2Division of Diabetes, Saiseikai Izuo Hospital, Osaka, Japan; 3Division of Internal Medicine, Daiwa Hospital, Osaka, Japan; 4Division of Internal Medicine, Meisai Kinen Hospital, Osaka, Japan; 5Division of Internal Medicine, Yukeikai Hospital, Neyagawa, Japan; 6Division of Internal Medicine, Katano Hospital, Katano, Japan; 7First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan; 8Second Department of Internal Medicine, Kansai Medical University, Hirakata, JapanCorrespondence: Shosaku Nomura, Center of Thrombosis and Hemostasis, Kansai Medical University Medical Center, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan, Tel + 81 6 6992 1001, Fax + 81 6 6992 1066, Email shosaku-n@mbp.ocn.ne.jpPurpose: In people with type 2 diabetes mellitus (T2DM), both glucose metabolism abnormalities and atherosclerosis risk are significant concerns. This study aims to investigate the effects of the sodium-glucose cotransporter 2 inhibitor tofogliflozin (TOFO) and the dipeptidyl peptidase-4 inhibitor anagliptin (ANA) on markers of glucose metabolism and atherosclerosis when administered individually or in combination.Methods: Fifty T2DM patients were divided into two groups (receiving either TOFO or ANA monotherapy) and observed for 12 weeks (observation points: 0 and 12 weeks). The TOFO and ANA groups were then further treated with ANA and TOFO, respectively, and the patients were observed for an additional 36 weeks (observation points: 24 and 48 weeks). Therapeutic effects and various biomarkers were compared between the two groups at the observation points.Results: Combination therapy led to significant improvements in HbA1c levels and atherosclerosis markers. Additionally, the TOFO pretreatment group exhibited significant reductions in sLOX-1 and IL-6 levels.Conclusion: The increase in sLOX-1 and IL-6 levels, which indicates the response of scavenger receptors to oxidized low-density lipoproteins in people with T2DM, is mitigated following TOFO and ANA combination therapy. TOFO alone or in combination with ANA may be beneficial for preventing atherosclerosis development in people with T2DM, in addition to its effect on improving HbA1c levels.Keywords: tofogliflozin, anagliptin, type 2 diabetes mellitus, atherosclerosis, soluble LOX-1

Shosaku Nomura,1 Takehito Taniura,2 Akira Shouzu,3 Seitaro Omoto,4 Masahiko Suzuki,5 Yoshinori Okuda,6 Tomoki Ito1 1First Department of Internal Medicine, Kansai Medical University, Hirakata, 2Division of Internal Medicine, Daiwa Hospital, Suita, 3Division of Internal Medicine, Saiseikai Izuo Hospital, Osaka, 4Division of Internal Medicine, Korigaoka Yukeikai Hospital, Hirakata, 5Division of Internal Medicine, Katano Hospital, Katano, 6Division of Internal Medicine, Meisei Memorial Hospital, Osaka, Japan Background: The aim was to evaluate the significance of arteriosclerosis obliterans-related biomarkers in patients with type 2 diabetes mellitus (T2DM), and to compare the effects of sarpogrelate, eicosapentaenoic acid (EPA) and pitavastatin on these markers. Patients and methods: Seventy-two arteriosclerosis obliterans patients with T2DM were classified into two groups, pitavastatin with either sarpogrelate (PS) or EPA (PE). We observed no differences in all biomarkers between the PS and PE groups before treatments. Results: The levels of body mass index, hemoglobin A1c, soluble E-selectin, soluble vascular cell adhesion molecule 1, plasminogen activator inhibitor-1 and platelet-derived microparticle in the PE group decreased significantly after treatment. The ankle branchial pressure index and adiponectin levels significantly increased in the PE group after treatment compared with the PS group. Conclusion: These results suggest that combination therapy using pitavastatin and EPA possesses an antiatherosclerotic effect and may be beneficial for prevention of vascular complications in patients with T2DM. Keywords: T2DM, pitavastatin, sarpogrelate, eicosapentaenoic acid, EPA, adiponectin, platelet-derived microparticle, PDMP

Yoshinori Okuda,1 Seitaro Omoto,2 Takehito Taniura,3 Akira Shouzu,4 Shosaku Nomura,51Division of Internal Medicine, Meisei Memorial Hospital, 2Division of Internal Medicine, Kohrigaoka Yukeikai Hospital, 3Division of Internal Medicine, Daiwa Hospital, 4Division of Internal Medicine, Saiseikai Izuo Hospital, 5First Department of Internal Medicine, Kansai Medical University, Osaka, Japan Background: Cardiovascular disease (CVD) is the main cause of death among hemodialysis (HD) patients. The effects of the dipeptidyl peptidase-4 inhibitor teneligliptin on CVD-related biomarkers in patients with type 2 diabetes mellitus (T2DM) receiving HD treatment are poorly understood. To determine whether teneligliptin has anti-CVD properties, we assessed its effects on soluble P-selectin (sP-selectin), platelet-derived microparticles (PDMPs), plasminogen activator inhibitor 1 (PAI-1), soluble E-selectin (sE-selectin), soluble vascular adhesion molecule 1 (sVCAM-1), and adiponectin plasma levels in HD and non-HD patients with T2DM. Methods: Patients with T2DM eligible for teneligliptin monotherapy or combination therapy (eg, teneligliptin plus a sulfonylurea) were administered teneligliptin (20 mg/d) once daily for 6 months. Plasma levels of sP-selectin, PDMPs, PAI-1, sE-selectin, sVCAM-1, and adiponectin were measured by enzyme-linked immunosorbent assay at baseline and after 3 months and 6 months of treatment. Results: Teneligliptin therapy significantly reduced plasma levels of sP-selectin, PDMPs, and PAI-1 compared with baseline levels, while significantly increasing adiponectin levels. sE-selectin and sVCAM-1 levels were significantly decreased only at 6 months. The reduction in sP-selectin, PDMPs, and PAI-1 was more significant in HD patients than in non-HD patients. However, the improvement in adiponectin levels was unchanged with HD treatment. Conclusion: By modulating PDMPs or PAI-1, teneligliptin shows an antiatherothrombotic effect that may be beneficial in the primary prevention of CVD in patients with T2DM on HD.Keywords: type 2 diabetes mellitus, teneligliptin, hemodialysis, PDMP, PAI-1

Seitaro Omoto,1 Takehito Taniura,2 Tohru Nishizawa,3 Takeshi Tamaki,3 Akira Shouzu,4 Shosaku Nomura3 1Division of Internal Medicine, Korigaoka Yukeikai Hospital, 2Division of Internal Medicine, Daiwa Hospital, 3First Department of Internal Medicine, Kansai Medical University, 4Division of Internal Medicine, Saiseikai Izuo Hospital, Osaka, Japan Background: Advanced glycation end products, selectins, and adiponectin play important roles in the development of atherosclerosis in individuals with diabetes. Sitagliptin has been shown to reduce the concentration of glycated hemoglobin in diabetic patients. However, its effects on soluble receptor for advanced glycation end products (sRAGEs), selectins, and adiponectin in these patients are poorly understood. This study was conducted to assess the effects of sitagliptin on the circulating levels of sRAGEs, monocyte chemoattractant protein-1 (MCP-1), selectins, and adiponectin in patients with type 2 diabetes. Methods: Diabetic patients eligible for sitagliptin monotherapy or combination therapy (eg, sitagliptin plus a sulfonylurea) were administered sitagliptin (50 mg/day) for 6 months. Levels of soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1), MCP-1, sRAGEs, and adiponectin were measured by ELISA at baseline and after 3 and 6 months of treatment. Results: At baseline, the levels of MCP-1, sP-selectin, sE-selectin, and sVCAM-1 were higher and the level of adiponectin was lower in diabetic patients than in nondiabetic patients. Sitagliptin therapy for 3 and 6 months significantly reduced plasma levels of sP-selectin, sE-selectin, sVCAM-1, and MCP-1 relative to baseline, while significantly increasing adiponectin levels. sRAGEs did not exhibit a statistical significance, although there was an increasing tendency. Furthermore, the reductions in sP-selectin, sE-selectin, sVCAM-1, and MCP-1 during sitagliptin therapy were significantly greater in responders, defined as patients with a significant increase in adiponectin levels, than in nonresponders. In contrast, responders showed a significant increase in the plasma concentration of sRAGEs. Conclusion: Sitagliptin shows an adiponectin-dependent anti-atherothrombotic effect, which may be beneficial for primary prevention of atherothrombosis, in patients with type 2 diabetes. Keywords: type 2 diabetes mellitus, sitagliptin, sRAGE, selectins, sVCAM-1, adiponectin

Shosaku Nomura1, Takehito Taniura2, Akira Shouzu3, Seitarou Omoto4, Norihito Inami4, Shinya Fujita1, Takeshi Tamaki1, Takashi Yokoi1, Toshiki Shimizu1, Tomoki Ito11First Department of Internal Medicine, Kansai Medical University, Osaka, Japan; 2Department of Internal Medicine, Ueda Hospital, Osaka, Japan; 3Department of Internal Medicine, Saiseikai Izuo Hospital, Osaka, Japan; 4Second Department of Internal Medicine, Kansai Medical University, Osaka JapanAbstract: The effects of statins on two platelet activation markers, plasiminogen activator inhibitor (PAI)-1 and adiponectin, were investigated in 68 patients with hyperlipidemia. The patients were treated with pitavastatin with a dosage of 2 mg daily. The plasma levels of platelet-derived microparticles (PDMP), soluble CD40 ligand (sCD40L), sP-selectin, PAI-1, and adiponectin were measured at baseline and after 6 months of treatment in both groups. In hyperlipidemic patients, the plasma levels were higher in PDMP, sCD40L, sP-selectin, and PAI-1, and lower in adiponectin, compared to the normolipidemic controls. Plasma PDMP and sCD40L were positively correlated, while plasma adiponectin was negatively correlated with the plasma levels of PAI-1. No significant differences were observed in the plasma levels of PDMP, sCD40L, sP-selectin, and PAI-1 before and after treatment. A significant increase in plasma adiponectin levels was observed after 6 months of treatment with pitavastatin. When the patients treated with pitavastatin were divided into two groups according to the adiponectin response to pitavastatin treatment, significant decreases in plasma PAI-1, PDMP, and sCD40L levels were observed after pitavastatin treatment in the responder group. These findings suggest that PDMP, sCD40L, and PAI-1 may participate in the development of atherothrombosis in patients with hyperlipidemia, and that pitavastatin may exert an adiponectin-dependent anti-atherothrombotic effect in hyperlipidemic patients.Keywords: hyperlipidemia, PAI-1, pitavastatin, adiponectin, atherothrombosis

Shosaku Nomura1, Seitaro Omoto2, Takashi Yokoi1, Shinya Fujita1, Ryotaro Ozasa1, Noritaka Eguchi3, Akira Shouzu31First Department of Internal Medicine, Kansai Medical University, 2Division of Internal Medicine, Korigaoka Yukeikai Hospital, 3Division of Internal Medicine, Saiseikai Izuo Hospital, Osaka, JapanBackground: Platelet-derived microparticles (PDMP), selectins, and adiponectin play an important role in the development of atherosclerosis in diabetes. Miglitol has been shown to have a beneficial effect on postprandial hyperglycemia in diabetic patients. However, its influence on platelet activation markers (PDMP and soluble CD40 ligand [sCD40L]), selectins, and adiponectin in these patients is poorly understood.Aim: We investigated the effect of miglitol on circulating levels of PDMP, sCD40L, selectins, and adiponectin in patients with type 2 diabetes.Methods: Miglitol (150 mg/day) was administered for 4 months. Levels of PDMP, sCD40L, soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), soluble L-selectin (sL-selectin), and adiponectin were measured by enzyme-linked immunosorbent assay at baseline, and after 1 and 4 months of treatment.Results: The levels of PDMP, sCD40L, sP-selectin, sE-selectin, and sL-selectin were higher in diabetic patients than in hypertensive patients, while there were no significant differences between hypertensive and hyperlipidemic patients. Before miglitol treatment, the adiponectin level of diabetic patients was lower than that of hypertensive patients. Miglitol therapy significantly decreased the plasma PDMP and sCD40L levels relative to baseline. Miglitol also caused a significant decrease of sP-selectin, sE-selectin, and sL-selectin. On the other hand, miglitol therapy led to a significant increase in adiponectin after 4 months of administration compared with baseline. Furthermore, the reduction of platelet activation markers and selectins during miglitol therapy was significantly greater in the responder (adiponectin-improved) group than the nonresponder group of diabetic patients.Conclusion: Miglitol has an adiponectin-dependent anti-atherothrombotic effect that may be beneficial for primary prevention of atherothrombosis in patients with type 2 diabetes.Keywords: platelet activation markers, atherothrombosis, platelet-derived microparticles, PDMP