Antiatherogenic Effect of Pioglitazone in Type 2 Diabetic Patients Irrespective of the Responsiveness to Its Antidiabetic Effect

Abstract

OBJECTIVE -Thiazolidinediones (TZDs), a class of insulin-sensitizing agents used clinically to treat type 2 diabetes, are also antiatherogenic. This study was designed to elucidate the relationship between the antiatherogenic and antidiabetic effects of pioglitazone, a TZD, in type 2 diabetic patients. RESEARCH DESIGN AND METHODS -A total of 136Japanese type 2 diabetic patients were included and divided into two groups: the pioglitazone-treated group (30 mg daily for 3 months) (n ϭ 70) and the untreated control group (n ϭ 66). The changes in glycolipid metabolism as well as plasma high-sensitivity C-reactive protein (CRP), leptin, adiponectin, and pulse wave velocity (PWV) were monitored to analyze the relationship between the antiatherogenic and antidiabetic effects of pioglitazone.RESULTS -The pioglitazone treatment significantly reduced hyperglycemia, hyperinsulinemia, and HbA 1c levels and increased plasma adiponectin concentrations relative to the control group (P Ͻ 0.01). It also significantly decreased CRP and PWV (P Ͻ 0.01). The antiatherogenic effect was observed in both the nonresponders showing Ͻ1% of reduction in HbA 1c (n ϭ 30) and responders showing Ͼ1% of reduction (n ϭ 40). ANCOVA revealed that treatment with pioglitazone was associated with a low CRP and PWV, independent of the changes in parameters related to glucose metabolism.CONCLUSIONS -This study represents the first demonstration of the antiatherogenic effect of pioglitazone in both nonresponders and responders with respect to its antidiabetic effect and suggests that pioglitazone can exert its antiatherogenic effect independently of its antidiabetic effect. Diabetes Care 26:2493-2499, 2003T ype 2 diabetes contributes to the risk of developing atherosclerotic diseases such as coronary heart disease and stroke and coronary restenosis after angioplasty or stenting (1-4). Therefore, it is of clinical importance to evaluate and treat cardiovascular complications in type 2 diabetic patients beyond glycemic control.Peroxisome proliferator-activated receptor-␥ (PPAR-␥) is a member of the nuclear receptor superfamily that, when activated by insulin sensitizers of the thiazolidinedione (TZD) class, including troglitazone, pioglitazone, and rosiglitazone, regulates a host of target genes (5,6). In humans with and animal models of insulin resistance and type 2 diabetes, TZDs can improve hyperglycemia and hyperinsulinemia and are currently used to manage type 2 diabetes (7). PPAR-␥ occurs abundantly in adipocytes where it regulates adipocyte differentiation (8), but it is also expressed in all major cell types participating in vascular injury, namely, endothelial cells, vascular smooth muscle cells (VSMCs), and macrophages (9,10). PPAR-␥ regulates the recruitment of monocytes to endothelial cells (11), modulates the inflammatory response in monocytes/macrophages and VSMCs (12-14), and inhibits macrophage foam cell formation and VSMCs proliferation and migration (13)(14)(15). In experimental models of atherosclerosis, ligandactivated PPAR-␥ prevents t...

The increase in abdominal subcutaneous fat depot is an independent factor to determine the glycemic control after rosiglitazone treatment

“…In this study, it was interesting that responders, defined as groups showing the best or good responses, were no more than 36.4%. This proportion was lower than that in previous studies (30,31). And the glycemic control in 16.8% of subjects was not improved, but rather aggravated.…”

“…Therefore, TZDs might be effective only in the specific population group. However, TZDs have reported having antiinflammatory or antiatherogenic effects in addition to hypoglycemic effect (30,32). Presumably, the adequate indication for using TZDs must be presented though well-controlled studies.…”

Impact of metabolic indices on central artery stiffness: independent association of insulin resistance and glucose with aortic pulse wave velocity

“…As the most predictive index of mortality, 2 h plasma glucose following a standard 75 g oral glucose tolerance test (2-HPG) may contribute to the pathogenesis of macrovascular disease more than fasting plasma glucose values (FPG) [2]. Premature conduit vessel arteriosclerosis predicts mortality in type 2 diabetes [3] and may be attenuated by therapeutic approaches with potential to lower glucose or blood pressure directly [4][5][6][7]. The independent association of FPG and 2-HPG indices with the haemodynamic consequence of early sclerosis (aortic stiffness) implies that modifiable structural mechanisms connect hyperglycaemia with vascular complications even within prediabetes thresholds of impaired glucose tolerance (IGT) [8][9][10][11] and impaired fasting glycaemia (IFG) [12,13].…”

The importance of treating multiple cardiometabolic risk factors in patients with Type 2 diabetes

“…The anti-atherogenic effects of pioglitazone were first demonstrated in a study involving 136 Japanese patients with Type 2 diabetes [66] . Treatment with pioglitazone significantly reduced CRP and increased adiponectin levels, but had no effect on leptin.…”

“…Furthermore, it appears that different antihyperglycaemic agents have different effects. Intensive blood glucose control with metformin in overweight patients with Type 2 diabetes produced a greater reduction in the risk of stroke compared with chlorpropamide, glibenclamide or insulin [65] , and the thiazolidinediones have demonstrated anti-atherogenic and anti-inflammatory effects [66][67][68][69][70] .…”