The effect of combining rosuvastatin with sartans of different peroxisome proliferator receptor-γ activating capacity on plasma 8-isoprostane prostaglandin F2a levels
BACKGROUND Statin therapy has been reported to be associated with new-onset diabetes. Angiotensin II-receptor blockers (ARBs) are effective antihypertensive drugs that have been reported to activate peroxisome proliferator-activated receptor gamma (PPARgamma) to differing extents, with favorable effects on glucose metabolism and the incidence of new-onset diabetes. Among the ARBs, telmisartan is a partial activator of PPARgamma, irbesartan is a weak partial activator, and olmesartan has no effect on PPARgamma activation. OBJECTIVE The goal of this study was to evaluate the effects on glucose homeostasis of combining rosuvastatin with ARBs of varying PPARgamma-activating potency in Greek adults with impaired fasting glucose, mixed dyslipidemia, and stage 1 hypertension. METHODS This was a 24-week, randomized, open-label study. Inclusion criteria were impaired fasting plasma glucose (FPG) (100-125 mg/dL [5.6-6.9 mmol/L]), mixed dyslipidemia (LDL-C >160 mg/dL [4.14 mmol/L] and triglycerides >150 mg/dL [1.69 mmol/L]), and stage 1 hypertension (systolic blood pressure 140-159 mm Hg and/or diastolic blood pressure 90-99 mm Hg). After 12 weeks of dietary intervention, patients were randomly allocated to receive rosuvastatin 10 mg/d plus telmisartan 80 mg/d (RT group), irbesartan 300 mg/d (RI group), or olmesartan 20 mg/d (RO group) for 24 weeks. The primary end point was change in the following indices of glucose metabolism after 6 months of treatment: FPG, homeostasis model assessment of insulin resistance (HOMA-IR), HOMA of beta-cell function (HOMA-B), and glycosylated hemoglobin (HbA(1c)). Secondary end points included changes in anthropometric variables, blood pressure, serum lipids, and high-sensitivity C-reactive protein (hs-CRP). Tolerability was monitored throughout the study. RESULTS After the 12-week dietary intervention, 151 white patients (78 female, 73 male) met the inclusion criteria and were randomized to receive RT (n = 52), RI (n = 48), or RO (n = 51). The mean (SD) age of the 3 groups was 60 (10), 60 (10), and 58 (12) years, respectively; their mean weight was 79 (11), 81 (12), and 78 (11) kg. At 6 months, the RT group had a 29% decrease in HOMA-IR (from a median [range] of 2.6 [0.6-6.6] to 1.8 [0.5-5.1]), the RI group had a 16% increase (from 2.5 [0.5-6.2] to 2.9 [0.5-8.1]), and the RO group had a 14% increase (from 2.4 [0.5-7.9] to 2.7 [0.5-5.2]) (all, P < 0.05 vs baseline). The improvement in the RT group was statistically significant compared with the RI group (P < 0.01) and the RO group (P < 0.05). The changes from baseline in FPG and HbA(1c) were not significant in any group. Fasting serum insulin decreased by 21% in the RT group (from 10.4 [2.4-28.1] to 8.2 [2.4-18.8] microU/mL), whereas it increased by 12% in the RI group (from 9.1 [2.0-26.5] to 10.2 [2.0-25.2] microU/mL) and by 8% in the RO group (from 10.1 [2.0-29.6] to 10.9 [2.0-19.1] microU/mL) (all, P < 0.05 vs baseline). Again, there was a significant difference between the RT group and the RI group (P < 0.01) and RO group (P < 0.05). Levels of hs-CRP decreased by 44% in the RT group (from 2.2 [0.3-7.9] to 1.2 [0.4-7.0] mg/L), by 12% in the RI group (from 2.2 [0.3-12.3] to 1.9 [0.2-11.4] mg/L), and by 22% in the RO group (from 2.1 [0.7-4.0] to 1.7 [0.7-6.2] mg/L). The difference was statistically significant for the RT group compared with baseline and with the RI and RO groups (all comparisons, P < 0.05). Blood pressure was significantly reduced from baseline in all 3 groups, with no significant differences between groups. No serious adverse events were reported during the study, nor were there any clinically significant elevations in aminotransferases or creatine kinase. CONCLUSION In this small, randomized, open-label study, the RT combination had favorable effects on HOMA-IR, fasting serum insulin, and hs-CRP compared with the RI and RO combinations in Greek adults with impaired fasting glucose, mixed hyperlipidemia, and stage 1 hypertension.