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vol. 9

Short communication
The effect of combining rosuvastatin with sartans of different peroxisome proliferator receptor-γ activating capacity on plasma 8-isoprostane prostaglandin F2a levels

Christos V. Rizos
Evangelos N. Liberopoulos
Constantinos C. Tellis
Alexandros D. Tselepis
Moses S. Elisaf

Arch Med Sci 2013; 9, 1: 172-176
Online publish date: 2013/02/21
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Hypercholesterolemia and high blood pressure are at the cornerstone of cardiovascular disease (CVD) development and progression and often coexist. In the context of comprehensive management [1, 2], the combination of a statin with an angiotensin receptor blocker (ARB) is common. Oxidative stress plays an important role in the pathogenesis and development of CVD [3, 4]. The isoprostanes are a family of eicosanoids of non-enzymatic origin produced by the random oxidation of tissue phospholipids by oxygen radicals. Levels of 8-isoprostane prostaglandin F2a (8-iso-PGF2a) have been established as a reliable marker of oxidative stress [5-7] and coronary heart disease [8]. Statins have a favorable or neutral effect on oxidative stress markers [9, 10]. The peroxisome proliferator receptor γ (PPAR-g) modifies the expression of numerous metabolic related genes and could therefore play a role in oxidative stress. Thiazolidinediones have been shown to hold antioxidative pleiotropic effects beyond glucose lowering [11, 12]. Some ARBs, mainly telmisartan and to a lesser degree irbesartan, have the ability to partially activate PPAR-g [13]. This trait of some ARBs may differentiate their effect on oxidative stress.

The present study evaluated the effects of combining a statin with ARBs of different capacity to activate PPAR-g on plasma 8-iso-PGF2a levels.

Material and methods


This is a pre-specified analysis of a previously reported study [14]. In brief, patients attending the Outpatient Lipid Clinic of the University Hospital of Ioannina, Greece were recruited. Eligible patients were those with impaired fasting plasma glucose, mixed dyslipidemia and stage 1 hypertension. Patients were excluded if they had any of the following: (1) history of diabetes, (2) history of CVD, (3) elevated triglycerides (TG) (> 400 mg/ dl; 4.52 mmol/l), (4) kidney disease, (5) hypothyroidism, (6) liver dysfunction, (7) receiving lipid-lowering or antihypertensive treatment in the last 3 months prior to recruitment and (8) females who did not take sufficient contraceptive measures.

All participants gave written informed consent and the study protocol was approved by our institutional ethics committee.

Study design

All patients (n = 159) received a 12-week dietary intervention in accordance with the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines and the Dietary Approaches to Stop Hypertension (DASH) diet [15]. Patients (n = 151) who continued to meet the inclusion criteria after the dietary intervention period were randomly allocated to open-label: i) rosuvastatin (10 mg/day) plus a sartan with partial PPAR-g activating capacity (telmisartan 80 mg/day; n = 52; RT group), ii) rosuvastatin (10 mg/day) plus a sartan with weak partial PPAR-g activating capacity (irbesartan 300 mg/day; n = 48; RI group) or iii) rosuvastatin (10 mg/day) plus a sartan without PPAR-g activating capacity (olmesartan 20 mg/day; n = 51; RO group).

Selected doses of studied drugs are the usual starting doses in clinical practice in our country. Moreover, selected sartan doses are equivalent in terms of blood-pressure lowering.

Compliance with study medication was assessed at week 24 by counting taken tablets; patients were considered compliant if they took 80-100% of the prescribed number of tablets.

Biochemical parameters

All laboratory determinations were carried out after an overnight fast as previously described [14] at baseline (which was after the 12-week dietary intervention) and at 6 months after initiation of treatment. Laboratory determinations were performed blindly with regard to treatment allocation. Plasma levels of 8-iso-PGF2a were determined by means of a competitive ELISA using a commercially available kit (Cayman Chemicals, Ann Arbor, MI) [16].

Statistical analysis

Values are given as mean ± standard deviation (SD) and median (range) for parametric and non-parametric data, respectively. Continuous variables were tested for lack of normality by the Kolmogorov-Smirnov test and logarithmic transformations were accordingly performed for non-parametric variables. The paired-sample t-test was used for assessing the effect of treatment in each group. Analysis of covariance (ANCOVA), adjusted for baseline values, was used for comparisons between treatment groups. Significance was defined as p < 0.05. Analyses were performed using the Statistical Package for the Social Sciences (SPSS) 15.0 (SPSS Inc, Chicago, IL). In a post hoc calculation, given the effect size, the alpha level, and the sample size, we calculate that the achieved power of this pre-specified analysis to find a significant difference for the 8-iso-PGF2a was above 95%.


A total of 159 patients (76 males, mean age 60 years) were enrolled. Of them, 151 (73 males, mean age 60 years) continued to meet the inclusion criteria after the dietary intervention period and were randomized to the 3 groups. No patient dropped out and compliance was > 80% in all patients. No significant differences regarding baseline data were found across groups (Table I). The effects of all combinations on metabolic parameters have been previously described [14]. In brief, after the study end no differentiation in anthropometric variables and blood pressure was observed between groups. In addition, lipid profile was similarly altered in all groups (Table II). However, the homeostasis model assessment insulin resistance (HOMA-IR) decreased only in the RT group while an increase was observed in the other 2 regimens (Table II).

Plasma levels of 8-iso-PGF2a vs. baseline decreased significantly only in the RT group (–8.6%; p = 0.02) (Table II). A non-significant trend for decrease vs. baseline was observed in the RI (–5.7%; p = 0.40) and RO (–3.7%; p = 0.60) groups (Table II). The changes of plasma 8-iso-PGF2a levels between groups were not significantly different (p = 0.70).


The combination of rosuvastatin with sartans of different PPAR-g activating capacity was associated with a decrease in levels of plasma 8-iso-PGF2a. However, this decrease reached significance only in the telmisartan group.

Statins have been shown to have either a beneficial or neutral effect on oxidative stress markers. Fluvastatin was shown to possess antioxidant properties [9], rosuvastatin was associated with only a trend for decreasing oxidative stress [10], while atorvastatin showed a neutral effect on oxidative status [17]. The activation of the renin-angiotensin system (RAS) has been shown to promote oxidative stress [18, 19]. As a result, ARBs may have beneficial effects on oxidative stress. Indeed, irbesartan [20] and olmesartan [21] have been associated with a decrease in oxidative stress markers, while eprosartan was not associated with any changes of 8-iso-PGF2a plasma levels [22]. Telmisartan was shown to decrease markers of oxidative stress vs. valsartan in type 2 diabetic patients with nephropathy [23].

Thiazolidinediones (TZDs), by activating PPAR-g, increase insulin sensitivity. Thiazolidinediones have been shown to hold antioxidative effects beyond glucose lowering [11, 12]. Telmisartan, which partially activates PPAR-g, may also possess additional antioxidative properties. The recent Effects of Simvastatin and Rosiglitazone Combination in patients with the metabolic syndrome (SIROCO) study showed that the combination of a statin (simvastatin) together with a PPAR-g agonist (rosiglitazone) decreased markers of oxidative stress [24]. By combining a commonly used statin (rosuvastatin) with telmisartan, which partially activates PPAR-g, an improvement of oxidative stress markers may be expected.

Indeed, a significant decrease in 8-iso-PGF2a was seen only in the rosuvastatin/telmisartan group in this study. Although all ARBs may have to some degree antioxidative effects, telmisartan may possess additional such effects since it can activate the PPAR-g receptors. On the other hand, this decrease was not significantly different when compared with the changes of 8-iso-PGF2a in the other 2 groups. This finding puts into question whether telmisartan is indeed different compared with the other 2 sartans. It should be noted that the baseline values of 8-iso-PGF2a were not particularly increased. Indeed, baseline levels of 8-iso-PGF2a were very close to the normal levels of 8-iso-PGF2a, which our group has measured using the same method in a previous study [7]. As a result, the potential of a drug treatment to further decrease the already near normal levels of 8-iso-PGF2a is diminished.

A limitation of our study was that no other markers of oxidative stress were determined. Another limitation was the small number of participants. Moreover, a control group receiving rosuvastatin as monotherapy was not included since it was considered unethical to further delay antihypertensive treatment in these high-risk patients. Additional limitations include the open-label design, the relatively short period of follow-up as well as the fact that no oral glucose tolerance test was performed in patients with impaired fasting glucose to identify diabetic patients.

In conclusion, the combination of rosuvastatin with sartans of different PPAR-g activating capacity was associated with a decrease in levels of plasma 8-iso-PGF2a. This decrease reached significance only in the telmisartan group.


 1. Katsiki N, Mikhailidis DP, Athyros VG, Hatzitolios AI, Karagiannis A, Banach M. Are we getting to lipid targets in real life? Arch Med Sci 2010; 6: 639-41.

 2. Athyros VG, Hatzitolios AI, Karagiannis A, et al. IMproving the imPlemEntation of cuRrent guidelines for the mAnagement of major coronary hearT disease rIsk factors by multifactorial interVEntion. The IMPERATIVE renal analysis. Arch Med Sci 2011; 7: 984-92.

 3. Madamanchi NR, Vendrov A, Runge MS. Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol 2005; 25: 29-38.

 4. Vassalle C, Petrozzi L, Botto N, Andreassi MG, Zucchelli GC. Oxidative stress and its association with coronary artery disease and different atherogenic risk factors. J Intern Med 2004; 256: 308-15.

 5. Morrow JD. The isoprostanes: their quantification as an index of oxidant stress status in vivo. Drug Metab Rev 2000; 32: 377-85.

 6. Milne GL, Musiek ES, Morrow JD. F2-isoprostanes as markers of oxidative stress in vivo: an overview. Biomarkers 2005; 10 Suppl 1: S10-23.

 7. Kostapanos MS, Spyrou AT, Tellis CC, et al. Ezetimibe treatment lowers indicators of oxidative stress in hypercholesterolemic subjects with high oxidative stress. Lipids 2011; 46: 341-8.

 8. Davies SS, Roberts LJ 2nd. F2-isoprostanes as an indicator and risk factor for coronary heart disease. Free Radic Biol Med 2011; 50: 559-66.

 9. Yilmaz MI, Baykal Y, Kilic M, et al. Effects of statins on oxidative stress. Biol Trace Elem Res 2004; 98: 119-27.

10. Agouridis AP, Tsimihodimos V, Filippatos TD, et al. The effects of rosuvastatin alone or in combination with fenofibrate or omega 3 fatty acids on inflammation and oxidative stress in patients with mixed dyslipidemia. Expert Opin Pharmacother 2011; 12: 2605-11.

11. Da Ros R, Assaloni R, Ceriello A. The preventive anti-oxidant action of thiazolidinediones: a new therapeutic prospect in diabetes and insulin resistance. Diabet Med 2004; 21: 1249-52.

12. Hwang J, Kleinhenz DJ, Rupnow HL, et al. The PPARgamma ligand, rosiglitazone, reduces vascular oxidative stress and NADPH oxidase expression in diabetic mice. Vascul Pharmacol 2007; 46: 456-62.

13. Benson SC, Pershadsingh HA, Ho CI, et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension 2004; 43: 993-1002.

14. Rizos CV, Milionis HJ, Kostapanos MS, et al. Effects of rosuvastatin combined with olmesartan, irbesartan, or telmisartan on indices of glucose metabolism in Greek adults with impaired fasting glucose, hypertension, and mixed hyperlipidemia: a 24-week, randomized, open-label, prospective study. Clin Ther 2010; 32: 492-505.

15. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med 2001; 344: 3-10.

16. Dounousi E, Papavasiliou E, Makedou A, et al. Oxidative stress is progressively enhanced with advancing stages of CKD. Am J Kidney Dis 2006; 48: 752-60.

17. Tycinska AM, Janica J, Mroczko B, et al. Hypotensive effect of atorvastatin in hypertensive patients: the association among flow-mediated dilation, oxidative stress and endothelial dysfunction. Arch Med Sci 2011; 7: 955-62.

18. Rueckschloss U, Quinn MT, Holtz J, Morawietz H. Dose-dependent regulation of NAD(P)H oxidase expression by angiotensin II in human endothelial cells: protective effect of angiotensin II type 1 receptor blockade in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 2002; 22: 1845-51.

19. Landmesser U, Cai H, Dikalov S, et al. Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 2002; 40: 511-5.

20. Sola S, Mir MQ, Cheema FA, et al. Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study. Circulation 2005; 111: 343-8.

21. Fliser D, Wagner KK, Loos A, Tsikas D, Haller H. Chronic angiotensin II receptor blockade reduces (intra)renal vascular resistance in patients with type 2 diabetes. J Am Soc Nephrol 2005; 16: 1135-40.

22. Rizos EC, Spyrou A, Liberopoulos EN, et al. Effects of eprosartan on serum metabolic parameters in patients with essential hypertension. Open Cardiovasc Med J 2007; 1: 22-6.

23. Galle J, Schwedhelm E, Pinnetti S, Boger RH, Wanner C. Antiproteinuric effects of angiotensin receptor blockers: telmisartan versus valsartan in hypertensive patients with type 2 diabetes mellitus and overt nephropathy. Nephrol Dial Transplant 2008; 23: 3174-83.

24. Lazich I, Sarafidis P, de Guzman E, Patel A, Oliva R, Bakris G. Effects of combining simvastatin with rosiglitazone on inflammation, oxidant stress and ambulatory blood pressure in patients with the metabolic syndrome: the SIROCO study. Diabetes Obes Metab 2012; 14: 181-6.
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