Deterioration of glucose homeostasis in type 2 diabetic patients one year after beginning of statins therapy
Highlights
► Simvastatin and rosuvastatin do not affect insulin-resistance in type 2 diabetes. ► Some evidence for negative effects on insulin secretion, impairing glucose control. ► Comparable effects on glucose regulation despite difference in LDL reduction. ► Confirmed beneficial effects of both statins on endothelium and inflammation.
Introduction
The role of statins in primary and secondary prevention of cardiovascular diseases (CVD), especially in patients with type 2 diabetes (T2D), is well established [1]. These beneficial effects are largely mediated by decreased LDL cholesterol along with several “pleiotropic” effects on endothelium, inflammation and plaque stability [2]. However, evidence from a number of randomized clinical trials over the last two decades highlighted a potential association between statin therapy and increased risk of development of diabetes [3], though this risk was low when compared with reduction in coronary events. Despite CVD account for most of deaths in people with diabetes, a potential deterioration of glycemic control in diabetic patients taking statins would be harmful in light of other diabetic complications (i.e. microvascular complications) which are more directly associated with an inappropriate glycemic control [4]. Beyond these observations from large clinical trials, a number of experimental studies, both in vitro and in vivo, have shown that certain statins, especially lipophilic ones, may have detrimental effects on glucose metabolism by several mechanisms, including the inhibition of both insulin secretion by pancreatic β-cells [5], [6] and insulin-induced glucose uptake in peripheral tissues [7], [8], [9]. Evidence from clinical studies in humans is more conflicting. The effects of simvastatin, a lipophilic statin, on glucose homeostasis have been investigated both in non-diabetic and diabetic individuals but results have been controversial [10], [11], [12], [13]. Moreover, in those studies which documented a detrimental effect of simvastatin on glucose control, it is unclear whether such an effect was driven by either a worsening of insulin-resistance or a deterioration of β cells insulin secretion. The potential diabetogenic effect of rosuvastatin, a hydrophilic statin with potent lipid-lowering action, has been substantially highlighted by the JUPITER study, which reported a worsening of glycated hemoglobin in non-diabetic patients treated with rosuvastatin for a median period of 1.9 years [14]. However, the influence of rosuvastatin on glucose control has still not been fully elucidated in diabetic patient even though, within the JUPITER trial, 77% of patients in the active group who developed diabetes in the follow-up had impaired fasting glucose at baseline, suggesting a worsening of glycemic control in subjects still at high risk for diabetes developing. In addition, the effects of rosuvastatin on insulin-resistance are still controversial [15], [16], since they have been investigated only after short periods of administration or employing surrogate measures of insulin sensitivity. According to this background, the present study aimed to evaluate the effects of rosuvastatin and simvastatin administration on euglycemic-hyperinsulinemic clamp-assessed insulin sensitivity, insulin secretion, glycated hemoglobin (Hb A1c) and fasting glucose, in patients with well-controlled T2D. As secondary outcomes, we evaluated the effects on endothelial function, leptin, adiponectin and inflammatory profile.
Section snippets
Study design and participants
This research was approved by the Independent Ethics Committee of the University Hospital “Policlinico Tor Vergata” (Rome, Italy) and conducted according to the Declaration of Helsinki. All the subjects enrolled gave their written informed consent. We designed a randomized, single blind with 2-period crossover intervention study. The allocation ratio was 1:1. All subjects were white Europeans and were recruited among individuals attending the outpatient service of the Diabetology Unit of the
Experimental results
As reported in Table 1, the final sample analyzed was constituted of 27 patients, aged 55.9 ± 2.6 (mean ± SD) years, 22 males, with a mean duration of diabetes of about 4 years. No significant difference in metformin dose was detected between groups. There were no significant differences between baseline characteristics of patients who initially had received either rosuvastatin (n = 14, Group 1) or simvastatin (n = 13, Group 2), except for HDL levels (lower in Group 1, p = 0.005). Patients did
Discussion
To our knowledge, this is the first clinical study demonstrating a worsening of glycemic control in patients with T2D after 12 months of statin administration, along with deterioration of β-cells function but without change in insulin sensitivity. Noteworthy, since patients were asked to maintain an isocaloric diet and usual daily physical activity throughout the study, no changes in weight or other body composition parameters which are known to interfere with insulin sensitivity were observed.
Conclusion
In the present study we observed that the potential diabetogenic effect of simvastatin and rosuvastatin is not driven by a detrimental effect on insulin sensitivity. Whilst a better characterization of β-cells function under statins administration is required, a deterioration of insulin secretion is likely to be mainly involved.
Acknowledgments
The present study has been supported by grants from: Fondazione Roma 2008 (Rome Foundation), Fondazione Umberto Di Mario, Ministry of University “Progetto di ricerca a rilevanza nazionale” 2008 and Ministry of Health “Ricerca Finalizzata” 2007.
The authors declare to have no financial and non-financial conflict of interest regarding this manuscript.
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