In the present study, our primary outcome of HbA1C levels was significantly increased in patients treated with atorvastatin. This was accompanied by increased fasting insulin levels, reduced insulin sensitivity, and lower adiponectin levels. Because HbA1C levels are a sensitive indicator of ambient glycemia, our results strongly suggest that atorvastatin causes glucose intolerance that is due, in part, to decreased insulin sensitivity. These off-target detrimental metabolic effects of atorvastatin occur despite beneficial effects to improve lipid profile, flow-mediated dilation, and circulating pro-inflammatory markers. Furthermore, there were no significant correlations between lipoprotein changes and endothelial dysfunction and metabolic parameters. We previously observed that simvastatin reduces adiponectin levels and insulin sensitivity (12
) and only pravastatin improved insulin sensitivity, even though both statins caused comparable improvements in lipid profiles and endothelium-dependent vasodilation in hypercholesterolemic patients (13
). Thus, different statins have differential metabolic effects that might depend on their lipophilic properties.
Statin therapy might directly alter adiponectin levels independent of adiposity. In 3T3-L1 adipocytes, pravastatin increases expression of adiponectin messenger ribonucleic acid and enhances adiponectin secretion into conditioned media. This corresponds to increased plasma levels of adiponectin and enhanced insulin sensitivity in C57BL/6J mice without changes in body weight (16
). Simvastatin inhibits the glucose-stimulated elevations of free calcium in beta cells, leading to suppressed insulin secretion (4
). Atorvastatin reduces sensitivity to insulin in rats (5
). Atorvastatin but not pravastatin attenuates expression of the glucose transporter GLUT-4 in adipocytes, impairing glucose tolerance (6
It is not clear why atorvastatin has beneficial metabolic actions in some studies but not in others.
The effects of atorvastatin might be different between patients with and without metabolic syndrome and diabetes. However, when we compared effects of atorvastatin on metabolic parameters in patients with and without metabolic syndrome and diabetes, there were no significant differences.
In the current study, the effects of atorvastatin on fasting glucose levels were not significant; however, the effects of atorvastatin on fasting insulin levels and HbA1C levels were significant when compared with placebo. The surrogate measure of insulin sensitivity we employed, QUICKI, is the most extensively validated and accurate surrogate index of insulin sensitivity currently available in humans; QUICKI measures primarily hepatic insulin resistance (15
). Under most conditions, peripheral and hepatic insulin sensitivity runs in parallel. Glycated hemoglobin A1C represents prevailing glycemia over long periods of time. Elevated HbA1C is a reflection of glucose intolerance. Glucose intolerance results from impaired insulin sensitivity and/or insulin secretion and/or non-insulin–mediated glucose disposal.
Clinical studies have demonstrated that lipophilic statins, atorvastatin, simvastatin, and rosuvastatin might increase the onset of new diabetes (7
). A nested case-control study reported that an adjusted odds ratio for simvastatin use alone compared with nonexposed odds ratio of 1.0 and for pravastatin use alone compared with nonexposed odds ratio of 0.7 (18
). Indeed, pravastatin reduces the rate of onset of new diabetes by 30% (19
), although it does not in another study (20
). Meta-analysis of randomized controlled trials suggests potential differences between statins (10
). Thus, it is possible that different statins might have differential effects on the rate of new onset diabetes, but to be certain, head-to-head comparative studies are required.
In patients with type 2 diabetes the benefits of lowering glucose levels by any means is unclear. In several recently published clinical trials, improving glycemic control did not reduce cardiovascular events (21
). This is a complicated issue. In patients with early reversible cardiovascular and metabolic pathophysiology benefits from lower glycemia might diminish cardiovascular risk (22
). However, in advanced patients with irreversible atherosclerotic disease, it might be unfavorable, due to hypoglycemia, weight gain, and other adverse effects (21
We reported that statin lowers CRP levels in hyperlipidemic coronary patients (23
). In the current study, we observed that atorvastatin lowers CRP levels relative to baseline levels in hyperlipidemic patients. However, these results did not achieve statistical significance when compared with placebo. This might be due, in part, to very low baseline CRP levels in our study subjects.