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Rosuvastatin and Metformin Decrease Inflammation and
Oxidative Stress in Patients With Hypertension and Dyslipidemia
Anel Gómez-García,a Gloria Martínez Torres,b Luz E. Ortega-Pierres,c Ernesto Rodríguez-Ayala,b
and Cleto Álvarez-Aguilard
aCentro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, Morelia,Michoacán, MéxicobUnidad de Investigación en Epidemiología Clínica, Hospital General Regional No. 1, Instituto Mexicano del Seguro Social, Morelia, Michoacán, MéxicocFacultad de Ciencias Médicas y Biológicas Dr. Ignacio Chávez, Universidad Michoacana de San Nicolásde Hidalgo, Morelia, Michoacán, MéxicodUnidad de Investigación Médica en Enfermedades Nefrológicas, Centro Médico Nacional Siglo XXI,Instituto Mexicano del Seguro Social, México DF, México Moreover, both rosuvastatin and metformin reduced Introduction and objectives. Both hypertension and
inflammation and oxidative stress. These results dyslipidemia raise the risk of cardiovascular disease demonstrate the presence of an additional because they have proinflammatory effects and increase cardioprotective effect, which may result from a direct oxidative stress. The aim of this study was to evaluate the mechanism of action or be a pleiotropic effect. Further effects of rosuvastatin and metformin on inflammation long-term studies are required to determine whether and oxidative stress in patients with hypertension and rosuvastatin or metformin can be used to decrease the cardiovascular risk resulting from oxidative stress and This open parallel-group clinical study involved 48 patients with hypertension and dyslipidemia.
Of these, 16 were treated with rosuvastatin, 10 mg/day, Key words: Oxidative stress. Inflammation. Drugs.
while 16 received metformin, 1700 mg/day, and the 14 in Pleiotropic effects. Cardiovascular risk.
the control group received starch placebo, 10 mg/day.
The following variables were recorded during the study:age, weight, body mass index, blood pressure, glucose, Rosuvastatina y metformina reducen la
total cholesterol, low-density lipoprotein (LDL) cholesterol, inflamación y el estrés oxidativo en pacientes
high-density lipoprotein (HDL) cholesterol, triglycerides, con hipertensión y dislipemia
interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα),glutathione reductase (GSH), glutathione peroxidase Introducción y objetivos. La hipertensión arterial
(GPx), and superoxide dismutase (SOD).
(HTA) y la dislipemia incrementan el riesgo de enferme- Results. Administration of 10 mg/day of rosuvastatin
dad cardiovascular a través de los efectos proinflamato- decreased total cholesterol by 41.7%, LDL cholesterol by rios y el estrés oxidativo. Nuestro objetivo fue estimar el 63.0%, and triglycerides by 10.7%, and increased HDL efecto de la rosuvastatina y la metformina en la inflama- cholesterol by 6.3%. Pharmacological treatment with ción y el estrés oxidativo en pacientes con HTA y dislipe- either rosuvastatin or metformin lead to reductions in IL-6, TNFα, GSH and GPx levels and an increase in the SOD Métodos. En un ensayo clínico abierto paralelo, se es-
level, and there were significant interactions between the tudió a 48 pacientes con HTA y dislipemia. Se trató a 16 two treatment groups for these variables.
pacientes con rosuvastatina 10 mg/día, 16 con metformi- Conclusions. Rosuvastatin improved the lipid profile.
na 1.700 mg/día y 16 con 10 mg de almidón como con-trol. Las variables analizadas durante el estudio fueronedad, peso, índice de masa corporal (IMC), presión arte-rial, glucosa, colesterol total (CT), de las lipoproteínas de SEE EDITORIAL ON PAGES 1220-2
baja densidad (cLDL) y de las lipoproteínas de alta densi-dad (cHDL), triglicéridos (TG), interleucina 6 (IL-6), factorde necrosis tumoral alfa (TNFα), glutatión reductasa(GSH), glutatión peroxidasa (GPx) y superóxido dismuta- This work was funded by the Fondo de Fomento a la Investigación (FOFOI, project No. IMSS-2004/030), Instituto Mexicano del Seguro Social.
Resultados. Con 10 mg/día de rosuvastatina, disminu-
yeron el CT (41,7%), el cLDL (63%) y los TG (10,7%) y Correspondence: Dr. A. Gómez García.
Avda. Madero Poniente, 1200 Centro. CP 58000 Morelia. se incrementó el cHDL (6,3%). Después del tratamiento farmacológico con rosuvastatina o metformina, se encon- tró disminución e interacción entre grupos en la IL-6, el Received April 5, 2007.
TNFα, la GSH y la GPx e incremento en la SOD.
Accepted for publication September 10, 2007.
Conclusiones. La rosuvastatina mejoró el perfil de lípi-
Rev Esp Cardiol. 2007;60(12):1242-9 Document downloaded from http://www.revespcardiol.org, day 07/10/2016. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
Gómez-García A et al. Rosuvastatin and Metformin Decrease Inflammation and Oxidative Stress dos. Ambos fármacos reducen la inflamación y el estrés stress regulation, in which oxidative and antioxidant oxidativo. Estos resultados demuestran un efecto adicio- enzymes take part, to be elucidated. However, a great nal cardioprotector, como un mecanismo de acción direc- deal of the information available is from laboratory to o a través de sus efectos pleiotrópicos. Son necesarios experiments, and much more work is required to clarify estudios adicionales a largo plazo para determinar si la the clinical significance of these drugs and their actions.
rosuvastatina o la metformina serán fármacos útiles paradisminuir el riesgo cardiovascular causado por el estrés The aim of this work was to determine the effects of oxidativo y la inflamación.
rosuvastatin and metformin on oxidative stress in patientswith HBP and dyslipidemia.
Palabras clave: Estrés oxidativo. Inflamación. Fármacos.
Efectos pleiotrópicos. Riesgo cardiovascular.
This open, parallel group study was performed between July and September 2006. The initial study subjects were510 patients with HBP and dyslipidemia selected from outpatients attending the Family Medicine Unit No. 80 HBP: high blood pressure of the Instituto Mexicano del Seguro Social (IMSS) in HDL-C: high density lipoprotein cholesterol Morelia, Michoacán, México. Of these, 244 were excluded IL-6: interleukin 6 since they had concomitant diabetes mellitus 2, and a LDL-C: low density lipoprotein cholesterol further 206 did not meet inclusion requirements since SOD: superoxide dismutase they were receiving pharmacological treatment for their TNFα: tumor necrosis factor alpha dyslipidemia or had been prescribed an excluded anti-hypertension treatment. Twelve patients declined toparticipate.
The inclusion criteria were: a) to have HBP (≥130/85 mm Hg) and dyslipidemia (LDL-C ≥100 mg/dL, triglycerides ≥150 mg/dL, HDL-C <40 mg/dL in men,or <50 mg/dL in women)16; b) to be receiving no In México, the prevalence of non-transmissible chronic pharmacological treatment for dyslipidemia; c) to be disease, such as high blood pressure (HBP) and diabetes receiving treatment for HBP with angiotensin converting mellitus, has grown exponentially over the last 2 decades.
enzyme inhibitors (ACEi); and d) to be ≥65 years o age.
Indeed, it is now more prevalent than transmissible disease.
Among the 48 patients who were finally included, The prevalence of HBP has reached 30.1%1 and is one none had modified their pharmacological treatment for of the main risk factors associated with cerebrovascular HBP, their diet, nor their physical activity routine in and coronary heart disease. It is thought that some 1.5% the 3 months prior to inclusion. No changes were made of all patients with HBP die each year for reasons directly during follow-up. The subjects were randomly assigned associated with this problem.1,2 to 3 pharmacological intervention groups. Sixteen patients Some 36.5% of all Mexican patients with HBP also received 10 mg/day rosuvastatin orally with their evening suffer dyslipidemia.1 This complication increases the risk meal (group GRos); 16 received metformin 1700 mg/day, of cardiovascular disease. One of the possible mechanisms administered as 2 tablets of 850 mg (in the first week 1 behind this lies in the proinflammatory effects of tablet/day was provided at breakfast and if tolerated this interleukin-6 (IL-6) and tumor necrosis factor (TNFα).
dose was increased to 1 tablet every 12 h) (group GMetf]); A number of studies have shown that both cytokines are and 16 received a starch placebo 10 mg/day (control involved in the associated chronic vascular inflammatory group [GC]). Treatment lasted 12 weeks (Figure 1). The reponse.3-5 Inflammation is a source of oxidative stress, minimum required sample size was estimated using the which is also involved in the development of clinical trial equation17; the result was required to provide atherosclerosis and HBP. Several studies indicate the a confidence level of 95%, and an 80% power to detect importance of a change in the balance of oxidative and a change in the serum IL-6 concentration of 0.6 pg/mL antioxidant enzymes in the progression of atherosclerosis, (standard deviation 0.5 pg/mL). The equation showed HBP, and diabetes mellitus type 2.6-8 13 patients per group were necessary. Sixteen were The additional actions of drugs that reduce the serum included in each to make up for any possible losses during concentration of lipids (statins)9-11 and improve sensitivity to insulin (metformin)12 are known as pleiotropic effects.
The patient variables recorded at the time of inclusion These include (among others) the improvement of were: age, body weight, height, body mass index (Quetelet endothelial function (via an anti-inflammatory and index), number of years with HBP, systolic blood pressure antioxidant action), the stabilization of atherosclerotic (SBP), diastolic blood pressure (DBP), total cholesterol plaques, and a reduction in the thrombogenic response.13-15 (TC), LDL-C, HDL-C, triglycerides (TG), serum This has allowed some of the mechanisms of oxidative concentrations of the inflammation markers IL-6 and Rev Esp Cardiol. 2007;60(12):1242-9 Document downloaded from http://www.revespcardiol.org, day 07/10/2016. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
Gómez-García A et al. Rosuvastatin and Metformin Decrease Inflammation and Oxidative Stress Assessment of Eligibility, n=510 Patients With HBP and Dyslipidemia Excluded, n=244Not Meet Inclusion Requirements, n=206Declined to Participate, n=12 Rosuvastatin 10 mg/day Metformin 1700 mg/day Placebo 10 mg/day Completed Treatment, n=16 Completed Treatment n=16 Completed Treatment, n=16 Lost to Follow-up, n=0 Lost to Follow-up, n=0 Lost to Follow-up, n=0 Treatment Suspended, n=0 Treatment Suspended, n=0 Treatment Suspended, n=0 Excluded From Analysis, n=0 Excluded From Analysis, n=0 Excluded From Analysis, n=0 Figure 1. Progress of patients through the study process.
TNFα, and oxidative stress (activities of the enzymes Blood Tests
glutathione reductase [GSH], glutathione peroxidase[GPx], and superoxide dismutase [SOD]). Patients Blood was collected between 7.00 and 8.00 am after attended a monthly appointment at the Epidemiological a 12 h fast and with the patients having rested for 20 min.
Research Unit, Clínica del Hospital General Regional All samples were collected by trained personnel. The No. 1 IMSS to check for any signs of adverse effects of samples were then centrifuged at 4000 rpm for 15 min treatment, to check adherence to treatment (via counting to extract the serum. Aliquots were prepared for the of the pills provided), to provide new prescriptions for determination of glucose, TC, LDL-C, HDL-C, and TG corresponding medication, and to check the patients had by enzyme colorimetry using the Dimension® AR Clinical not changed their lifestyles or had been prescribed Chemistry System. The remaining aliquots were stored additional pharmacological treatment that might affect at –70oC until they were analyzed for IL-6, TNFα, GSH, their lipid or inflammatory status or oxidative stress GPx, and SOD by ELISA (Cayman Chemical®). The intra-analysis coefficient of variation for all tests was At the end of the intervention period all patient variables (see above) were rechecked in all 3 study groups. Allpatients received strict clinical monitoring, with particular attention paid to liver enzymes levels.
The main adverse effects checked for were gastric The results are expressed as means (standard deviation).
intolerance of the drugs provided and/or liver enzyme The Student t test for paired samples was used to examine levels three times the normal laboratory-reported limits.
the differences in serum lipids before and after the All patients were fully informed about the study and pharmacological interventions. Differences between provided their written consent to be included; all were means were analyzed by 2-way ANOVA followed by the allowed to abandon the study at any time. This work was Bonferroni test. The dependent variables were the approved by the Ethics Committee of the Hospital General concentrations of IL-6, TNFα, and oxidative stress Regional No. 1 del Instituto Mexicano del Seguro Social enzymes; the different treatments and times (before and in Morelia, Michoacán, México.
after treatment) were taken as independent variables. Rev Esp Cardiol. 2007;60(12):1242-9 Document downloaded from http://www.revespcardiol.org, day 07/10/2016. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
Gómez-García A et al. Rosuvastatin and Metformin Decrease Inflammation and Oxidative Stress TABLE 1. Baseline Clinical and Biochemical Characteristics of the Patients
GRos (n=16)
GMetf (n=16)
GC (n=16)
P (ANOVA)
Age, mean (SD), y YWHBP indicates years with high blood pressure; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TC, total cholesterol; GC, control group; GMetf, metformin group; GRos, rosuvastatin group; BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure; TG, triglycerides.
TABLE 2. Markers of Inflammation and Concentration of Oxidative Stress Enzymes at the Beginning
of Treatment
GRos (n=16)
GMetf (n=16)
GC (n=16)
P (ANOVA)
A P value less than .05 was considered significant. All In the GRos group, treatment reduced the TC by 41.7%, calculations were performed using SPSS v.12.0 software LDL-C by 63%, and TG by 10.7%, and increased HDL-C for Windows (Chicago, Illinois, USA).
by 6.3%. In contrast, in the GMetf group there was ageneral trend towards an increase in serum lipids,especially LDL-C which showed an 11.8% increase.
Figure 3 shows the effect of the different treatments No patients were lost to follow-up nor was there any in terms of serum IL-6 and TNFα concentration. In the need to suspend treatment in any patient during the 12 GRos group, IL-6 was reduced by 22.24% and TNFα by week experimental period. Treatment was well tolerated, 13.03%; in the GMetf group IL-6 was reduced by 26.73% no patient declared any adverse effect, and no significant and TNFα by 8.31% (P<.05 for all comparisons). Two- modifications in liver enzyme values were seen. Tables 1 way ANOVA revealed an interaction between the groups and 2 show the clinical, biochemical and inflammation, with respect to IL-6 (F=3.19; P=.045) and TNFα (F=8.01; and oxidative stress marker results for the patients at the P=.004), and significant differences between the groups start of the study. The values of all variables across the GRos and GMetf compared to GP after 3 months with groups were similar at this time.
respect to IL-6 (F=12.50; P<.0001) and TNFα (F=3.12; A post-treatment reduction in body weight was seen in the GRos (80.57 [12.83] kg before treatment, 79.27 Finally, Figure 4 shows the change in oxidative stress [12.52] kg after treatment; P=.013) and GMetf subjects markers for each group. The activities of GSH and GPx (before treatment 80.97 [10.22] kg, after treatment 74.7 were both significantly reduced and SOD activity [10.44] kg; P=.011), and therefore in their BMI (GRos significantly increased by the GRos and GMetf treatments.
before treatment 33.05 [4.09] kg, after treatment 33.37 Two-way ANOVA revealed an interaction between the [3.62] kg [P=.002]; GMetf before treatment 34.39 [3.83] groups with respect to GSH (F=4.46; P=.014), GPx kg, after treatment 32.41 [4.79] kg [P=.015]). No (F=8.04; P=.0006), SOD (F=5.56; P=.008) and significant significant changes in body weight nor BMI were seen differences between the groups GRos and GMetf and GP in the GC subjects.
after 3 months of treatment with respect to the same Figure 2 shows the percentage modification of the oxidative stress enzymes (GSH, F=17.74; P<.0001; GPx, serum lipid profiles with respect to each treatment group.
F=11.38; P<.0001; SOD, F=9.11; P=.0004).
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Gómez-García A et al. Rosuvastatin and Metformin Decrease Inflammation and Oxidative Stress centage Change in Lipids, % –55 F=12.50; P<.0001 centage Change in Lipids, % F=3.12; P<.048 Figure 3. Modification of inflammation following 12 weeks of treatment.
Two-way ANOVA (differences between GRos and GMetf compared to
GC). GC indicates control group; GMetf, metformin group; GRos, rosuvastatin group.
centage Change in Lipids, % Statins (inhibitors of HMG-CoA reductase) can induce large reductions in the concentration of plasma lipids; Figure 2. Percentage modification of lipids after 12 weeks of treatment.
they are therefore the treatment of choice for patients A: rosuvastatin group. B: metformin group. C: control group.
with hypercholesterolemia or high LDL-C concentrations.
HDL-C indicates high density lipoprotein cholesterol; LDL-C, low densitylipoprotein cholesterol; TC, total cholesterol; TG, triglycerides.
In the present study, significant reductions were seen inboth TC and LDL-C concentrations following treatmentwith rosuvastatin (10 mg/day) However, it should benoted that this response was seen with a dose of just (10 mg/day); in other studies18,19 such a response has only been seen with larger doses, which can be associatedwith more intense adverse effects. In the present work Treatment with oral rosuvastatin (10 mg/day) for no patient reported any adverse event attributable to 3 months reduced the patients'TC, TG, and LDL-C levels, rosuvastatin, nor were any changes seen in the liver moderately increased the HDL-C level, and reduced the enzymes that might indicate a modification of hepatic levels of inflammation and oxidative stress markers.
function. The mechanism of action of this drug and of Treatment with oral metformin (1700 mg/day) had a the statins in general involves the reduction of TC and similar effect on the latter variables, but induced non- LDL-C via the inhibition of hepatic cholesterol synthesis, significant increases in lipid profile variables, especially and by increasing the expression of liver LDL-C receptors that favor the capture of this compound.
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Gómez-García A et al. Rosuvastatin and Metformin Decrease Inflammation and Oxidative Stress accompanied by weight loss.20 This hypothesis mayreceive some support from the reductions observed in serum IL-6 and TNFα, cytokines related to inflammation, and insulin resistance.21 Although it has been reported that metformin can reduce plasma lipid values,22-24 in the present study no significant differences in serum lipid values were seenin the group treated with this drug. In agreement, Kiayias et al25 reported metformin to have no effect on plasma lipid levels. The main metabolic effect of metformin is the improvement in sensitivity to insulin of the liver andperipheral tissues. The beneficial effect of metformin in terms of the reduction of body weight and of pro-insulin- like molecules has been reported.26,27 In the present study, F=17.74; P<.0001 treatment with metformin 1700 mg/day led to a significant reduction in BMI; this agrees with that reported in other clinical studies28,29 and confirms that previously reported by our group30 - that the most important effects ofmetformin are weight loss, the modification of bodycomposition, an increase in glucose uptake in hypoglycemic patients, and hyperinsulinemia and the improvement of beta cell function. Several authors haveshown metformin eliminates plasminogen activator inhibitor 1 and macrophage migratory inhibition factorfrom the plasma of obese patients; this drug may therefore have anti-inflammatory activity and reduce cardiovascular F=11.38; P<.0001 High blood pressure is reported to promote the endothelial expression of cytokines such as IL-6 and α, which mediate the amplification of proinflammatory signals33 and participate in thedevelopment of atherosclerosis.34,35 There is therefore growing interest in the pleiotropic effects of drugs such as the statins and36-38 and metformin,39 which might helpmodulate oxidative stress and the inflammatory response (known cardiovascular risk factors). In the present work, the administration of rosuvastatin or metforminsignificantly reduced serum IL-6 and TNFαconcentrations. The reduction of these inflammation markers is probably due to a reduction in the activity of F=9.11; P<.0004 nuclear factor kappa B (NF-κB) and an increase in theactivity of the protein Akt (as seen in monocyte cultures).39-41 Evidence has accumulated in recent years that NF-κB Figure 4.Modification of markers of oxidative stress after 12 weeks of
is a common denominator in the coordinated expression treatment. Two-way ANOVA (differences between GRos and GMetf of genes induced by inflammatory processes associated compared to GC). GC indicates control group; GMetf, metformin group;GRos, rosuvastatin group.
with endothelial activation.42 Unlike other transcriptionfactors, the activation of NF-κB requires no induction ofgene expression.
It is known that in patients with HBP, hyperglycemia, and dyslipidemia increase oxidative stress. In the present An interesting finding was the moderate loss of body study, treatment with rosuvastatin or metformin led to a weight (2.8 kg) associated with rosuvastatin treatment.
reduction of this stress. This might be explained by a This is thought to be the first report associating statin direct effect of these drugs on the suppression of NF-κB, treatment with such weight loss. It may be that by reducing thus reducing inflammation and the production of reactive the serum lipid concentration sensitivity to insulin is oxygen species,41,43,44 or by their regulating the activity improved. In patients with HBP and dyslipidemia it is of SOD, which would help protect against oxidative common that a reduction in insulin resistance be Rev Esp Cardiol. 2007;60(12):1242-9 Document downloaded from http://www.revespcardiol.org, day 07/10/2016. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
Gómez-García A et al. Rosuvastatin and Metformin Decrease Inflammation and Oxidative Stress Limitations of the Study
10. Nazzaro P, Manzari M, Merlo M, Triggiani R, Scarano A, Ciancio L, et al. Distinct and combined vascular effects of ACE blockade This study has several limitations. For example, body and HMG-CoA reductase inhibition in hypertensive subjects.
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