Blood Pressure Control and Inflammatory Markers in Type 2 Diabetic Patients Treated with Pioglitazone or Rosiglitazone and Metformin

387 Hypertens Res Vol.30 (2007) No.5 p.387-394 Original Article Blood Pressure Control and Inflammatory Markers in Type 2 Diabetic Patients Treated with Pioglitazone or Rosiglitazone and Metformin Giuseppe DEROSA1), Elena FOGARI1), Arrigo F. G. CICERO2), Angela D’ANGELO1), Leonardina CICCARELLI1), Mario N. PICCINNI1), Fabio PRICOLO1), Sibilla A. T. SALVADEO1), Alessia GRAVINA1), Ilaria FERRARI1), and Roberto FOGARI1) The aim of the study was to assess the effects of the combination of metformin plus pioglitazone or rosiglitazone on glucose and blood pressure in type 2 diabetic patients with metabolic syndrome, as well as its tolerability in those patients. In this 12-month, multicentric, double-blind, randomized, controlled, parallelgroup trial, all patients began with metformin. Patients were randomized for self-administration of either pioglitazone or rosiglitazone for 12 months. We assessed body mass index (BMI), glycemic control (glycosylated hemoglobin [HbA1c], fasting and postprandial plasma glucose and insulin levels [FPG, PPG, FPI and PPI, respectively] and homeostasis model assessment [HOMA] index) and systolic and diastolic blood pressure (SBP and DBP, respectively), at baseline and at 3, 6, 9 and 12 months of treatment, as well as highsensitivity C-reactive protein (hs-CRP), nitrites/nitrates and adiponectin (ADN) at baseline and at 12 months of treatment. Significant HbA1c decreases were obtained after 9 (p < 0.05) and 12 (p < 0.01) months in both groups. After 9 and 12 months, mean FPG and PPG levels were decreased in both groups (p < 0.05 and p < 0.01, respectively). We observed decreases in FPI and PPI at 9 and 12 months (p < 0.05 and p < 0.01, respectively) compared to the baseline values in both groups. Furthermore, HOMA index improvement over the baseline value was obtained only at 12 months (p < 0.05) in both groups. SBP and DBP improved significantly (p < 0.05, for each) in both groups after 12 months. hs-CRP decreased significantly (p < 0.05) in both groups after 12 months; nitrites/nitrates and ADN increased significantly (p < 0.05, for each) in both groups after 12 months. The combination of thiazolinediones and metformin is associated with a slight but significant improvement in the long-term blood pressure control of these patients, and with an improvement in the anti-inflammatory state, both of which are related to a similar reduction in insulin-resistance. (Hypertens Res 2007; 30: 387–394) Key Words: thiazolidinediones, pioglitazone, rosiglitazone, metformin, diabetes mellitus From the 1)Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; and 2)G. Descovich Atherosclerosis Study Center of the D. Campanacci Clinical Medicine and Applied Biotechnology Department, University of Bologna, Bologna, Italy. Address for Reprints: Giuseppe Derosa, M.D., Ph.D., Department of Internal Medicine and Therapeutics, University of Pavia, P. le C. Golgi, 2–27100 Pavia, Italy. E-mail: Received September 12, 2006; Accepted in revised form December 26, 2006. 388 Hypertens Res Vol. 30, No. 5 (2007) Introduction Coronary artery disease (CAD) is the leading cause of serious morbidity and mortality in patients with diabetes, who have a two- to four-fold increased risk of CAD (1). This heightened risk is strongly related not only to the inadequate control of glycemia but also to other cardiovascular risk factors, and in particular to arterial hypertension (2). For these reasons, the American Diabetes Association (ADA) has suggested the vigorous treatment of both hyperglycemia and high blood pressure using any available means (3). For patients not taking insulin, accumulating evidence suggests that combination therapy using oral antidiabetic agents with different mechanisms of action may be highly effective for achieving and maintaining target blood glucose levels, perhaps reducing the high secondary failure rate of monotherapy (4). In the course of the disease, the use of combinations of oral agents may delay the need for insulin while maintaining glycemic control, thus making aggressive oral treatment more acceptable for many patients (5). Metformin is a biguanide antihyperglycemic drug that has been used to treat type 2 diabetes mellitus for over 40 years, and its main mechanism of action is to counteract peripheral insulin-resistance (6). Moreover, metformin is the only antihyperglycemic drug demonstrated to have relevant positive effects on hard clinical outcomes: it prevented approximately 40% of vascular events in a large retrospective Canadian study carried out on more than 12,000 patients (7), it significantly reduced any diabetes-related endpoint in the United Kingdom Prospective Diabetes Study (8) and it decreased the incidence of diabetes by 31% in the large Diabetes Prevention Program (9). Thiazolidinediones are a more recent class of oral hypoglycemic agents. The hypoglycemic effect of thiazolidinediones is related to their ability to increase insulin sensitivity and, consequently, to increase peripheral glucose utilization. Although the exact mechanism of action is not completely understood, the most widely accepted hypothesis is that their effect on insulin sensitivity is related to their well-known ability to bind and activate the nuclear peroxisomal proliferator–activated receptors-γ (PPAR-γ) (10). Some studies have shown that the combination of thiazolidinediones and metformin improved glycemic control in type 2 diabetic patients (11, 12). Although the metabolic effect of thiazolidinediones has been adequately studied and many data on their effect on blood pressure are available, few data can be found on a headto-head comparison between pioglitazone and rosiglitazone in combination with metformin. Furthermore, few data exist on inflammation markers related to the use of these treatments. Thus, the aim of our study was to compare the long-term effects of pioglitazone and rosiglitazone on blood pressure control and on inflammation markers of diabetic patients treated with metformin. Methods Study Design This 12-month, multicentric, double-blind, randomized, controlled, parallel-group trial was conducted at the Department of Internal Medicine and Therapeutics, University of Pavia (Pavia, Italy); and at the G. Descovich Atherosclerosis Study Center of the D. Campanacci Clinical Medicine and Applied Biotechnology Department, University of Bologna (Bologna, Italy). The study protocol was approved at each site by institutional review boards and was conducted in accordance with the Declaration of Helsinki and its amendments. Patients Caucasian patients aged ≥ 18 years of either sex were eligible for inclusion in the study if they had type 2 diabetes mellitus according to ADA criteria (13) (duration, ≥ 6 months), and if they had poor glycemic control (glycosylated hemoglobin [HbA1c] level, > 7.5%) or had experienced adverse effects with diet and oral hypoglycemic agents, such a (...truncated)