Readers wishing to see the figures/tables for this paper should consult the print version.

Low-grade inflammation has been shown to be an important risk factor for the development of cardiovascular complications,¹ besides lowdensity lipoprotein (LDL) cholesterol. 3-Hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) are currently the most frequently used pharmacologic intervention in patients at risk for cardiovascular disease. In addition to their beneficial effect on the atherogenic lipid profile, they exert anti-inflammatory actions by activating peroxisome proliferator-activated receptor (PPAR)γ receptors.²

Thiazolidinediones (TZDs) are a class of antidiabetic drugs that have been shown to reduce the incidence of cardiovascular complications in patients with type 2 diabetes.^3,4 Thiazolidinediones activate PPARγ receptors, improving insulin sensitivity of adipose tissue, hepatocytes, and the endothelium of the vascular wall.⁵ In addition to improving glucose control, they have a broad range of anti-inflammatory and pleiotrophic properties. As shown in the Table, both statins and TZDs exert complementary effects on a large spectrum of major cardiovascular risk factors.

The acute phase inflammatory protein, high-sensitivity C-reactive protein (hs-CRP), has been shown to be a valuable predictor of cardiovascular events.⁶ Most patients with cardiovascular disease are characterized by the metabolic syndrome and more or less distinct insulin resistance accompanied by enhanced inflammatory activity and an increase in matrix-degrading matrix metalloproteinases (MMPs).⁷ Adiponectin, mainly secreted from the subcutaneous adipose tissue, has been shown to serve as an important mediator in the progression of insulin resistance, the metabolic syndrome, and increased cardiovascular risk.^8,9 Adiponectin has been shown to directly increase insulin sensitivity, to improve endothelial function, and to exert several anti-oxidative, anti-atherogenic, and anti-inflammatory effects.^10-12 In addition to increasing adiponectin levels, PPARα and PPARγ stimulation increases the expression of adiponectin receptors in macrophages and might therefore provide substantial therapeutic effects in the development and progression of atherosclerosis.¹³

Furthermore, insulin resistance and the lipid triad (small, dense LDL cholesterol level; low high-density lipoprotein [HDL] cholesterol level; and high triglyceride level) are common findings in these patients. This complex cluster of risk factors cannot be covered with a statin or a TZD alone. Therefore, we evaluated whether the combination of a well-established statin, simvastatin (Zocor), in combination with a clinically proven TZD, pioglitazone (Actos), is more effective than either agent alone in reducing low-grade inflammation and improving the overall risk profile in subjects without diabetes but with increased cardiovascular risk.

Subjects and methods

The study design was a 3-arm, double-blind, randomized trial comparing monotherapy with 40 mg simvastatin, monotherapy with 45 mg pioglitazone, and the combination of both, with measurements of target parameters at baseline and after 12 weeks of treatment.¹⁴ A total of 135 eligible subjects with proven cardiovascular disease and/or hypertension and an hs-CRP level from ≥ 1 mg to < 10 mg/L were recruited for study participation. Subjects were excluded if they had received statin therapy within the previous 4 weeks before randomization, had chronic inflammatory diseases, or had known or newly diagnosed diabetes. Metabolic syndrome was diagnosed according to the American Heart Association/ National Heart, Lung, and Blood Institute criteria.¹⁵ At baseline and after 3 months of treatment, hs-CRP, MMP-9, plasminogen activator inhibitor (PAI)-1, and macrophage chemoattractant protein (MCP)-1 plasma levels were measured, and insulin sensitivity was estimated by homeostasis model assessment (HOMA).

Results

In accordance with previous studies, hs-CRP was decreased by 19% with simvastatin and by 33% with pioglitazone treatment (Figure 1). One of the most important findings of our study was that the combination of simvastatin and pioglitazone exerted an additive effect, resulting in a decrease in hs-CRP of 43%. However, this additive effect of both drugs was only significant when compared with simvastatin monotherapy. As shown in Figure 2, the change in insulin resistance correlated with changes in hs-CRP.

Pioglitazone significantly reduced PAI-1, whereas simvastatin alone or combined with pioglitazone had only minor, nonsignificant effects on PAI-1. Matrix metalloproteinase-9 activity was significantly reduced by the TZD in monotherapy as well as in the combination therapy, whereas an increase in MMP-9 was observed with simvastatin. Neither pioglitazone nor simvastatin had an effect on MCP-1. The changes in major metabolic parameters and body weight are shown in the Table. Fasting plasma glucose and glycosylated hemoglobin showed a slight but statistically significant decrease only with pioglitazone monotherapy. Insulin resistance was significantly reduced by pioglitazone monotherapy, whereas no effect of simvastatin was shown. Adiponectin levels increased during pioglitazone monotherapy and during treatment with combination therapy. Surprisingly, treatment with simvastatin alone resulted in a small but significant reduction in adiponectin levels. Body weight increased significantly in both pioglitazone-treated groups but remained unchanged in the simvastatin group. As expected, simvastatin significantly decreased LDL cholesterol and increased HDL cholesterol levels with no add-on effect in combination therapy with pioglitazone. However, only combined treatment with simvastatin and pioglitazone was effective in reducing triglyceride levels.

All treatment regimens were generally well tolerated. As in previous studies, the most frequent side effects of pioglitazone were weight gain and the development of peripheral edema. Treatment with pioglitazone as monotherapy and in combination was associated with a higher incidence of peripheral edema (11.4% and 22.2%, respectively) than simvastatin monotherapy (0 %; P = .713 vs pioglitazone monotherapy and P = .07 vs pioglitazone combination therapy) and was also associated with significant increases in body weight and body mass index (P < .01).

Discussion

This study was the first to show that pioglitazone reduces hs-CRP and other inflammatory parameters in subjects without diabetes but with cardiovascular disease and increased low-grade inflammation. The reduction of hs-CRP was comparable to that of 40 mg simvastatin, a statin with proven vasoprotective potency.¹⁶ Pioglitazone also significantly reduced MMP-9 and PAI-1 levels, whereas simvastatin did not. Because the subjects did not have diabetes, the effects of pioglitazone cannot be attributed to a substantial improvement in glucose control, as was discussed in the report of the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) Study, which included subjects with type 2 diabetes.³

In contrast to simvastatin, pioglitazone significantly improved insulin resistance. Compared with healthy subjects, our cardiovascular risk population was characterized by increased hs-CRP levels, a high prevalence of the metabolic syndrome (48.7%), and increased insulin resistance as measured by HOMA. As shown in Figure 2, the reduction in hs-CRP was significantly correlated with a decrease in insulin resistance during pioglitazone treatment. Insulin resistance of the endothelium plays a major role in the pathogenesis of atherosclerotic lesions.¹⁷ Thus, it appears that the improvement in insulin sensitivity may be linked to low-grade inflammation. In a recent meta-analysis of 7 clinical studies on the effect of thiazolidinedione treatment on risk reduction of repeat target vessel revascularization following percutaneous coronary intervention, TZDs reduced reocclusion in subjects with diabetes by 66% (95% confidence interval [CI], 0.19-0.63) and without diabetes by 63% (95% CI, 0.18-0.77).¹⁸ The authors of this meta-analysis attributed this therapeutic effect on the vessel wall to an improvement in insulin sensitivity.

Decreased levels of adiponectin have been found in individuals with obesity, atherosclerosis, and insulin resistance, suggesting its deficiency may have a causal role in the pathogenesis of these diseases.¹² Besides increasing adiponectin levels, PPARα and PPARγ stimulation increases the expression of adiponectin receptors in macrophages and might therefore produce substantial therapeutic effects in the development and progression of atherosclerosis.¹³

Thus, there remains the question of whether it is advisable to add a TZD to therapy for high-risk cardiovascular patients receiving statin treatment. Our data clearly show that in this population with increased cardiovascular risk, simvastatin reduced LDL cholesterol levels and significantly increased HDL cholesterol levels, which was not observed during monotherapy with pioglitazone. Otherwise, treatment with pioglitazone was found to improve insulin sensitivity, increase adiponectin levels, and reduce associated inflammatory markers. In the majority of subjects, monotherapy with simvastatin or pioglitazone monotherapy did not result in a target level of hs-CRP below 1 mg/L. However, the combination of both drugs was more effective in reducing hs-CRP than simvastatin alone. Even more importantly, there was complementary activity of both drugs on a broad spectrum of cardiovascular risk factors, from correction of insulin resistance, with its multiple harmful effects on low-grade inflammation and vascular cell responses, to the correction of an atherogenic lipid profile. This improvement was shown without an increase in adverse side effects.

Conclusions

We evaluated the potential benefit of monotherapy with pioglitazone or combination therapy with simvastatin and pioglitazone in subjects without diabetes but with high cardiovascular risk and activated inflammation. Pioglitazone significantly improved insulin resistance and reduced parameters of low-grade vascular inflammation. Combination therapy with simvastatin had additive effects on low-grade inflammation and complementary actions on a broad spectrum of cardiovascular risk factors. Thus, TZDs should be considered as an additional pharmacologic approach in improving cardiovascular risk profile, even in patients with ongoing statin treatment.

References