Combined effects of atorvastatin and metformin on glucose-induced variations of inflammatory process in patients with diabetes mellitus

Abstract

Background

Statin treatment improves survival in patients with atherosclerosis, but their effect on the glucose-induced variations of inflammatory markers, is unknown. We examined the effect of combined therapy with atorvastatin and metformin on glucose-induced variations of inflammatory molecules in patients with newly diagnosed diabetes mellitus type 2 (DM).

Methods

Thirty five subjects with newly diagnosed DM were randomized to receive metformin 850 mg/d (M, n = 17) or metformin 850 mg/d + atorvastatin 10 mg (n = 18). All subjects underwent glucose loading (75 g oral glucose) at baseline and after 12 weeks of treatment. Blood samples were obtained at baseline and 3 h post-loading, while serum tumor necrosis factor alpha (TNF-α) levels were determined at baseline and at 3 h.

Results

Serum TNF-α remained unchanged in metformin at baseline (1.36 ± 0.18 to 1.47 ± 0.21 pg/ml p = NS) and after treatment (1.44 ± 0.71 to 1.31 ± 0.17 pg/ml, p = NS), while it was reduced in metformin + atorvastatin (2.3 ± 0.3 to 2.0 ± 0.4 pg/ml, p = NS at baseline and 1.80 ± 0.2 to 1.65 ± 0.2 pg/ml, p = 0.03 after treatment).

Conclusions

Interestingly, the combination of metformin and atorvastatin partly prevents the glucose-loading induced elevation of glucose levels (at 1 h), suggesting a better response to glucose intake than monotherapy with metformin. In addition, combined treatment with atorvastatin and metformin reduces the post-glucose loading levels of TNF-α compared to metformin monotherapy.

Introduction

Inflammation is considered to be a key feature in the process of atherogenesis in patients with diabetes mellitus (DM) type 2 [1]. Studies have shown that increased levels of several markers of inflammation like tumor necrosis factor alpha (TNF-α) are highly produced in patients with diabetes mellitus and these levels generally correlate with markers of glycemic control, such as glycosylated hemoglobin A1c (HbA1c) [1], [2], [3]. Such inflammatory markers have been found to be elevated in states of insulin resistance, while playing important role in predicting cardiovascular risk [4], [5].

Diabetes mellitus is strongly associated with coronary artery disease (CAD), especially with the progression of atherosclerosis and several mechanisms have been proposed to be responsible for the unfavorable effects of diabetes on coronaries as well as peripheral arteries [6], [7], [8]. In states of diabetes, the risk of developing coronary and peripheral arterial disease increases up to 4-fold [9]. Statins have been found to be beneficial in treating diabetics [10]. In addition, recent studies have shown that statin treatment is also beneficial in managing patients with DM, not only through their hypolipidemic effects, but also through a number of pleiotropic effects, which are able to control the multifactorial atherosclerosis observed in DM [11]. Moreover, large clinical trials have demonstrated that statin treatment improves survival in patients with atherosclerosis and reduces the risk of cardiovascular disease in diabetes [12], [13]. However, whether statin treatment is beneficial in glucose metabolism and in the glucose-induced variations of inflammatory process in diabetes is still unknown and remains to be seen.

In the present study we examined the effect of atorvastatin when administered on top of conventional anti-diabetic treatment with metformin, on the glucose-induced variations of inflammatory process in patients with newly diagnosed diabetes mellitus type 2. We also compared the effect of this combination therapy on inflammatory process with that of monotherapy with metformin.