Comparison of the Effects of Simvastatin vs. Rosuvastatin vs. Simvastatin/Ezetimibe on Parameters of Insulin Resistance

E. Moutzouri; E. Liberopoulos; D. P. Mikhailidis; M. S. Kostapanos; A. A. Kei; H. Milionis; M. Elisaf

Disclosures

Int J Clin Pract. 2011;65(11):1141-1148. 

In This Article

Discussion

In the present study, we compared the effects of three different regimens that reduce LDL-C comparably on HOMA-IR and other indices of glucose metabolism in patients with primary hypercholesterolemia. All three hypolipidemic regimens, namely rosuvastatin 10 mg, simvastatin 40 mg and simvastatin/ezetimibe 10/10 mg were associated with significant increases in HOMA-IR and fasting insulin levels compared with baseline. No difference among the three hypolipidemic treatments was noted.

Large-scale clinical trials as well as meta-analyses have demonstrated that statin therapy may be associated with adverse effects on glucose metabolism.[1–5] It has been suggested that various statins may differentially affect glucose metabolism.[4,15] However, data from head-to-head comparisons of different statins and/or the combination of a statin with ezetimibe, are lacking. Our study is the first to compare the effects of rosuvastatin 10 mg, simvastatin 40 mg and simvastatin/ezetimibe 10/10 mg on indices of glucose metabolism.

The effects of rosuvastatin on glucose metabolism are under scrutiny. In the JUPITER trial, the effects of rosuvastatin 20 mg were compared with placebo in 17,802 patients with LDL-C < 130 mg/dl and hsCRP >2 mg/l.[2] At 1.9 years, rosuvastatin administration reduced the primary end point (myocardial infarction, stroke, arterial revascularisation, hospitalisation for unstable angina or death from cardiovascular causes) by 44%. However, rosuvastatin treatment was associated with a significant increase in physician-reported newly diagnosed diabetes compared with placebo.[2] We have previously demonstrated that rosuvastatin administration in hypercholesterolemic patients with IFG induced a dose-dependent increase in HOMA-IR and fasting insulin levels.[6,7] In accordance, a very recently published study showed that rosuvastatin 40 mg daily for 6 weeks significantly increased fasting insulin levels.[16] On the other hand, no detrimental effect of rosuvastatin 10 or 20 mg on HOMA-IR was demonstrated in other studies.[17–19] What is more, a very recently published study evaluated the effects of rosuvastatin 10 mg and atorvastatin 20 mg daily for 12 weeks on glucose metabolism in nondiabetic dyslipidemic patients. In this study, rosuvastatin significantly decreased HOMA-IR and fasting insulin levels compared with baseline and atorvastatin.[19] Of note, no control group was included.[19]

Data on the effect of simvastatin on glucose metabolism are contradictory. A retrospective analysis of the HPS (Heart Protection Study) demonstrated no effect of simvastatin 40 mg on the incidence of NOD compared with placebo.[20] In accordance, the PIOglitazone and STATin (PIOSTAT) study also suggested a neutral effect of simvastatin on glucose metabolism.[21] In a randomised study in prediabetic overweight hypercholesterolemic patients, simvastatin did not change insulin resistance as assessed by HOMA-IR levels.[22] On the other hand, several studies have reported an adverse impact of simvastatin on glucose metabolism in non-diabetic hyperlipidemic patients.[23,24] In line, a recent meta-analysis examining the effects of different statins on insulin sensitivity in 1146 patients suggested that simvastatin may deteriorate insulin resistance.[4]

The mechanisms by which statins may impair glucose metabolism are not known. One possibility is a statin-mediated decrease in various metabolic products of the mevalonate pathway, such as the isoprenoids farnesyl pyrophosphate (FPP) or geranylgeranylpyrophosphate (GGPP). These isoprenoid molecules have been linked with the upregulation of the membrane transport protein glucose transporter 4 (GLUT4) in 3T3-L1 adipocytes, thus augmenting glucose uptake.[25] In addition, a possible role for the small GTP binding proteins as regulators of the glucose-mediated insulin secretion by b cells has been suggested.[26] Statins, by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, decrease the production of these substances. This could imply a class effect operative through metabolic products of the mevalonate pathway. However, as mentioned above and discussed below, data show that heterogeneity among statins may exist.

The lipophilicity of individual statins may influence their effects on carbohydrate metabolism. Specifically, it has been suggested that lipophilic statins inhibit glucose-induced cytosolic Ca2+ signalling and insulin secretion by blocking L-type Ca2+ channels in b-cells.[27] However, this opposes the observed effects of rosuvastatin, which is known to be a hydrophilic molecule. Freeman et al. demonstrated a protective effect of pravastatin, which is a hydrophilic statin, on progression to diabetes in a post hoc analysis of West of Scotland Coronary Prevention Study (WOSCOPS).[15] In the multivariate Cox model, baseline BMI, log triglyceride and baseline glucose remained significant predictors, but systolic blood pressure and log white blood cells were no longer significant. Pravastatin therapy also remained a significant predictor with a multivariate hazard ratio of 0.70 (95% CI 0.50–0.99, p = 0.042).[15] We failed to find any difference between simvastatin 40 mg compared with rosuvastatin 10 mg regarding their effects on glucose metabolism indices.

Ezetimibe decreases cholesterol absorption by inhibiting intestinal Niemann-Pick C1 Like 1 (NPC1L1) protein. Ezetimibe administration may favourably affect glucose metabolism, as supported by animal and human studies.[9–11,28] Hiramitsu et al. reported that in hypercholesterolemic Japanese individuals, ezetimibe significantly reduced fasting insulin and HbA1c levels, whereas adiponectin levels, which are inversely correlated with insulin resistance, increased.[10] In a recently published study, ezetimibe significantly decreased HOMA-IR compared with controls.[11] It was hypothesised that combining ezetimibe with a statin may counterbalance the possible adverse effects induced by statins on glucose metabolism. Dagli et al. showed that combining low dose pravastatin (10 mg) with ezetimibe (10 mg) resulted in significant reduction in insulin resistance compared with pravastatin 40 mg.[29] On the other hand, Her et al. demonstrated that the combination of atorvastatin (5 mg) with ezetimibe (5 mg) did not affect HOMA-IR, fasting insulin levels or HbA1c levels compared with atorvastatin 20 mg or rosuvastatin 10 mg daily for 8 weeks in 90 hypercholesterolemic patients. In this study, a significant though small increase in HbA1c was observed with atorvastatin monotherapy.[18] In line, no effect was observed in insulin resistance by the combination of simvastatin with ezetimibe in another study.[30] Specifically, there was no change in HOLA-IR and area under the curve (AUC) of insulin and adiponectin levels in both the monotherapy group with simvastatin 20 mg and the combination group in prediabetic hypercholesterolemic patients.[30] In our study, there was no difference between ezetimibe/simvastatin and statin monotherapy groups. This may imply that the possible statin-mediated increase in insulin resistance is not specifically statin- or dose-dependent, and the addition of ezetimibe does not alter this increase.

Study Limitations and Strengths

The main limitation of our study is the lack of a control group. Therefore, we cannot exclude the potential for false positive findings. However, it was deemed necessary to start hypolipidemic treatment following a 3-month period of lifestyle changes if treatment targets had not been reached. Additional limitations include its open-label design and the relatively short period of follow-up (12 weeks). No oral glucose tolerance test (OGTT) was performed in patients with IFG to identify diabetic patients. The patients were predominantly female and therefore our findings may not be generalisable.

The method of assessing insulin resistance, HOMA-IR, is a widely used and sensitive method. However, hyperinsulinemic-euglycemic clamp and hyperglycemic clamp, is considered the gold standard for measuring insulin sensitivity and insulin secretion respectively.

On the other hand, this was an adequately powered study, and laboratory parameters were blindly assessed with regard to treatment allocation. Moreover, all comparisons were adjusted for baseline levels.

Whether increases in HOMA-IR would result in different rates of NOD is not known. Larger studies in prediabetic patients, which include the occurrence of NOD as an end point are needed.

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