Comparison of the effects of simvastatin vs. rosuvastatin vs. simvastatin/ezetimibe on parameters of insulin resistance

Authors


  • Disclosures The authors state no conflict of interest and have received no payment in preparation of this manuscript. Some of the authors (EL, DM, HM and EM) have given talks, attended conferences and participated in trials and advisory boards sponsored by various pharmaceutical companies.

Moses Elisaf, MD, FASA, FRSH, Professor of Internal Medicine, Department of Internal Medicine, School of Medicine, University of Ioannina, 45 110 Ioannina, Greece
Tel.: + 302651007509
Fax: + 302651007016
Email: egepi@cc.uoi.gr

Summary

Background:  Statin treatment may be associated with adverse effects on glucose metabolism. Whether this is a class effect is not known. In contrast, ezetimibe monotherapy may beneficially affect insulin sensitivity.

Objective:  The aim of this study was to compare the effects of three different regimens of equivalent low-density lipoprotein cholesterol (LDL-C) lowering capacity on glucose metabolism.

Methods:  A total of 153 patients (56 men), who had not achieved the LDL-C goal recommended by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) despite a 3-month dietary and lifestyle intervention, were randomly allocated to receive open-label simvastatin 40 mg or rosuvastatin 10 mg or simvastatin/ezetimibe 10/10 mg for 12 weeks. The primary end point was changes in homeostasis model assessment of insulin resistance (HOMA-IR). Secondary endpoints consisted of changes in fasting insulin levels, fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c), the HOMA of β-cell function (HOMA-B) (a marker of basal insulin secretion by pancreatic β-cells), LDL-C and high sensitivity C reactive protein (hsCRP).

Results:  At week 12, all three treatment regimens were associated with significant increases in HOMA-IR and fasting insulin levels (p < 0.05 compared with baseline). No significant difference was observed between groups. No change in FPG, HbA1c and HOMA-B levels compared with baseline were noted in any of the three treatment groups. Changes in serum lipids and hsCRP were similar across groups.

Conclusion:  To the extent that simvastatin 40 mg, rosuvastatin 10 mg and simvastatin/ezetimibe 10/10 mg are associated with adverse effects on insulin resistance, they appear to be of the same magnitude.

What’s known

  •  In the Justification for the use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, an increase in the incidence of new-onset diabetes associated with rosuvastatin treatment was observed.
  •  Concerns that statins may be associated with mild adverse effects on glucose metabolism have been raised. However, data are inconclusive.
  •  Whether this is a class effect remains unknown.
  •  Small studies have suggested that ezetimibe may be associated with beneficial effects on glucose metabolism.

What’s new

  •  This is the first study directly comparing the effects of simvastatin 40 mg, rosuvastatin 10 mg and simvastatin/ezetimibe 10/10 mg on glucose metabolism in non-diabetic patients with dyslipidaemia.
  •  All three hypolipidemic measurements were associated with increases in HOMA-IR (a marker of insulin resistance) and fasting insulin levels compared with baseline. No difference between ezetimibe/simvastatin and statin monotherapy groups was noted.
  •  The clinical relevance of these findings remains unknown.

Introduction

Statins are the cornerstone of both primary and secondary cardiovascular disease (CVD) prevention. However, concerns were recently raised regarding the effects of statins on carbohydrate metabolism (1). In the Justification for the use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial an increase in the incidence of new-onset diabetes (NOD) associated with rosuvastatin treatment was observed (2). Several meta-analyses have been conducted to elucidate the effect of statins on glucose metabolism (3–5). Treatment with statins has been associated with a 9% increase in the risk of developing NOD without any differential effect among individual statins (3,5). However, another meta-analysis showed that there may be differences among various statins (4). In the latter meta-analysis, pravastatin appeared to improve insulin sensitivity, whereas simvastatin was associated with an adverse effect on glucose metabolism (4). Also, atorvastatin and rosuvastatin non-significantly worsened insulin sensitivity (4). We have previously shown that rosuvastatin administration in hypercholesterolemic patients with impaired fasting glucose (IFG) was associated with a dose-dependent increase in insulin resistance (6,7).

Ezetimibe is a cholesterol absorption inhibitor, which is mainly used in combination with statins. The combination of ezetimibe with low dose of statin results in similar low-density lipoprotein cholesterol (LDL-C) lowering compared with a high dose of the same statin (8). Some studies have suggested that treatment with ezetimibe may be associated with beneficial effects on glucose metabolism (9–11).

Simvastatin 40 mg, rosuvastatin 10 mg and the combination of simvastatin 10 mg with ezetimibe 10 mg result in LDL-C reductions of approximately the same magnitude (12,13). However, the effects of these treatments on glucose metabolism have not been directly compared.

The present study compared the effects of simvastatin 40 mg, rosuvastatin 10 mg and simvastatin/ezetimibe 10/10 mg on indices of glucose metabolism in Greek hypercholesterolemic patients.

Methods

Study population

Consecutive patients with primary hypercholesterolemia (n = 160) attending the Outpatient Lipid and Obesity Clinic of the University Hospital of Ioannina, Ioannina, Greece participated in the present study.

Inclusion criteria were LDL-C levels above those recommended by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) based on each patient risk factors following a 3-month period of lifestyle changes (14).

Exclusion criteria were known CVD, symptomatic carotid artery disease, peripheral arterial disease, abdominal aortic aneurysm, diabetes mellitus, triglycerides > 500 mg/dl (5.65 mmol/l), renal disease (serum creatinine levels > 1.6 mg/dl; 141.4 μmol/l), hypothyroidism [thyroid stimulating hormone (TSH) > 5 IU/ml] and liver disease [alanine aminotranferase and/or aspartate aminotranferase levels > 3-fold upper limit of normal (ULN) in two consecutive measurements], neoplasia as well as clinical and laboratory evidence of an inflammatory or infectious condition. Patients with hypertension were included in the study if they were on stable medication for at least 3 months and their blood pressure was adequately controlled (no change in their treatment was allowed during the study). Patients currently taking lipid-lowering drugs or having stopped them less than 4 weeks before study entry were excluded.

Study protocol

Before randomisation to study treatment, all patients underwent a 12-week dietary intervention in accordance with the NCEP-ATP-III guidelines (14). After 12 weeks, patients who continued to meet the inclusion criteria were randomly allocated to receive open-label simvastatin 40 mg or rosuvastatin 10 mg or simvastatin/ezetimibe 10/10 mg for 12 weeks. Patients were instructed to follow the same diet guidelines during drug treatment. Randomisation was performed by means of a computer-generated sequence of random numbers.

All participants gave their written informed consent before any clinical or laboratory evaluations were performed. The study protocol was approved by the institutional ethics committee.

Primary and secondary end points

The primary end point was change in the homeostasis model assessment of insulin resistance (HOMA-IR) after 3 months of treatment among the three study groups. Secondary end points included changes in fasting plasma glucose (FPG), fasting insulin, glycosylated haemoglobin (HbA1c), the HOMA of β-cell function (HOMA-B) (a marker of basal insulin secretion by pancreatic β-cells), serum lipid parameters and high sensitivity C-reactive protein (hsCRP) among the three study groups. Tolerability was assessed by questioning patients about adverse effects and monitoring relevant laboratory parameters [creatine kinase (CK), liver function tests].

Compliance with study medication was assessed at week 12 by tablet counts; patients were considered compliant if they took 80–100% of the prescribed number of tablets.

Clinical and laboratory assessments

Visits took place at baseline, after the 12-week dietary intervention period and at 12 weeks after drug treatment commenced.

Blood samples were obtained after a 14 h overnight fast and were blindly assessed with regard to treatment allocation. All laboratory measurements were performed at the Laboratory of Biochemistry of the University Hospital of Ioannina. Fasting insulin levels were measured using an AxSym microparticle enzyme immunoassay on an AxSym analyzer (Abbott Diagnostics, Abbott Park, IL, USA). HOMA-IR was calculated as follows: fasting insulin (mU/l) × fasting glucose (mg/dl)/405. HOMA-B was calculated as follows: (360× fasting insulin [mU/l])/(fasting glucose [mg/dl] −63). HbA1c (expressed as percentage of the total haemoglobin concentration) was determined using a latex agglutination inhibition assay (Randox Laboratories Ltd., Crumlin, UK). The analytical range for total Hb is 7–23 g/dl. The range of the HbA1c assay is approximately 0.252.4 g/dl. The analytical range for %HbA1c is the concentration that corresponds to the level 6 HbA1c calibrator (2.40 g/dl HbA1c, 17.1% HbA1c at a total Hb of 14 g/dl). The minimum detectable concentration of HbA1c with an acceptable level of precision was determined as 0.25 g/dl. The inter- and intra-assay % coefficient of variation (CV) for all other measurements was < 5.0%. Accuracy and precision was surveyed by both, internal quality controls and external quality control assurance.

Concentrations of FPG, total cholesterol (TC), triglycerides (TGs) and high-density lipoprotein cholesterol (HDL-C) were determined enzymatically on the Olympus AU 600 clinical chemistry analyser (Olympus Diagnostica, Hamburg, Germany). HDL-C was determined using a direct assay (Olympus Diagnostica). LDL-C was calculated with the Friedewald formula.

Apolipoproteins (apo) A-I and apoB and apoE, as well as lipoprotein a [Lp(a)] were measured using a Behring Nephelometer BN100 and with reagents (antibodies and calibrators) from Dade Behring Holding GmbH (Liederbach, Germany). The apoA-I and apoB assays were calibrated according to the International Federation of Clinical Chemistry standards. Serum creatinine, liver and muscle enzymes as well as thyroid function tests were measured using conventional methods. Serum concentrations of hsCRP were measured using the high sensitivity CRP method (Dade Behring, Marburg, Germany) based on particle enhanced immunonephelometry; the reference range is 0.175–55 mg/l.

Statistical analysis

It was estimated that a sample size of 150 would give a 90% power to detect a 15% difference in the change of HOMA-IR between the three groups at a two-sided alpha of 0.05. Parametric and non-parametric data are presented as mean (SD) and media (range) respectively. The chi-square test was used to compare categorical variables. Continuous variables were tested for lack of normality using the Kolmogorov–Smirnov test, and logarithmic transformations were performed for non-parametric variables. The paired-samples t test was used to assess the effects of treatment in each group. Analysis of covariance (ANCOVA), adjusted for baseline values, was used for comparisons between groups.

After log-transforming non-Gaussian variables, Pearson correlation coefficients were used to describe the relationship of post-treatment change in the HOMA-IR with baseline HOMA-IR, age, gender as well as with waist circumference, body mass index (BMI), hsCRP, lipid and apolipoprotein levels and changes in these parameters at the end of follow up (univariate analysis).

Statistical significance was set at p < 0.05 (two-tailed). Analyses were performed using spss version 15.0 (SPSS Inc., Chicago, IL, USA).

Results

Recruitment took place from July 2009 through July 2010. Initially, 160 patients were enrolled. After a 12-week dietary intervention, 153 patients (56 male) continued to meet the inclusion criteria and were randomised to receive either simvastatin 40 mg (n = 55) or rosuvastatin 10 mg (n = 45) or the combination of simvastatin 10 mg with ezetimibe 10 mg (n = 53).

The clinical characteristics of study participants are listed in Table 1. The baseline clinical and laboratory characteristics did not significantly differ between groups (Tables 1–4).

Table 1.   Baseline clinical characteristics of study participants
 Simvastatin (n = 55)Rosuvastatin (n = 45)Simvastatin/Ezetimibe (n = 53)p
  1. *All values are expressed as mean ± SD for continuous variables and number of patients (percent) for categorical variables.

  2. ACEIs, angiotensin converting enzyme inhibitors, ARBs, angiotensin II receptor blockers; BMI, body mass index; MetSyn, metabolic syndrome [diagnosed by the NCEP-ATP-III criteria (14)].

Age, years58 ± 852 ± 1660 ± 8ns
Male gender, n (%)18 (33)17 (37)21 (39)ns
Postmenopausal females, n (% of females)19 (51)15 (53)16 (50)ns
BMI, kg/m229 ± 829 ± 929 ± 8ns
Waist circumference, cm99 ± 1099 ± 1097 ± 10ns
Hypertension (%)141211ns
Smokers (%)665ns
MetSyn (%)202325ns
Current medication
 ACEIs/ARBs1098ns
 Β-blockers232ns
 Diuretics777ns
 Aspirin222ns
Table 2.   Indices of glucose metabolism at baseline and after 12 weeks of treatment
 BaselineWeek 12p vs. baseline
  1. *All values are expressed as mean ± SD except for fasting serum insulin, HOMA-IR and HOMA-B which are expressed as median (range). FPG, fasting plasma glucose; HbA1c, glucosylated haemoglobin; HOMA-IR, homeostasis model assessment of insulin resistance; HOMA-B, HOMA of β-cell function; Rosuva, rosuvastatin; Simva/Eze, simvastatin/ezetimibe; Simva, simvastatin.

FPG, mg/dl
 Simva 40 mg92 ± 1195 ± 11ns
 Rosuva 10 mg96 ± 998 ± 11ns
 Simva/Eze 10/10 mg94 ± 996 ± 10ns
Fasting serum insulin, μU/ml
 Simva 40 mg4.8 (4.6–7.0)6.1 (5.3–8.0)0.02
 Rosuva 10 mg5.8 (5.2–9.0)7.0 (6.0–10)0.03
 Simva/Eze 10/10 mg4.4 (4.8–9.0)6.0 (5.8–9.6)0.03
HOMA-IR
 Simva 40 mg1.1 (1.1–1.6)1.4 (1.2–1.9)0.02
 Rosuva 10 mg1.4 (1.2–2.1)1.6 (1.5–2.6)0.03
 Simva/Eze 10/10 mg1.0 (1.1–2.3)1.5 (1.4–2.5)0.03
HOMA-B
 Simva 40 mg71 (22–180)65 (21–170)ns
 Rosuva 10 mg55 (18–352)74 (17–237)ns
 Simva/Eze 10/10 mg62 (19–234)70 (17–155)ns
HbA1c, %
 Simva 40 mg6.0 ± 0.35.9 ± 0.5ns
 Rosuva 10 mg5.9 ± 0.15.8 ± 0.4ns
 Simva/Eze 10/10 mg6.0 ± 0.35.8 ± 0.3ns
Table 3.   Serum lipid parameters at baseline and after 12 weeks of treatment
 BaselineWeek 12p vs. baseline
  1. *All values are expressed as mean ± SD except for triglycerides, Lp(a) and hs-CRP, which are expressed as median (range).

  2. Apo, apolipoprotein; HDL, high-density lipoprotein; hs-CRP, high sensitivity C reactive protein; LDL, low-density lipoprotein; Lp(a), lipoprotein (a); Rosuva, rosuvastatin; Simva/Eze, simvastatin/ezetimibe; Simva, simvastatin.

Total cholesterol, mg/dl
 Simva 40 mg256 ± 41176 ± 31< 0.001
 Rosuva 10 mg274 ± 41185 ± 26< 0.001
 Simva/Eze 10/10 mg263 ± 39171 ± 24< 0.001
LDL cholesterol, mg/dl
 Simva 40 mg176 ± 3499 ± 26< 0.001
 Rosuva 10 mg182 ± 3399 ± 24< 0.001
 Simva/Eze 10/10 mg177 ± 3391 ± 20< 0.001
Triglycerides, mg/dl
 Simva 40 mg111 (55–241)93 (54–200)< 0.001
 Rosuva 10 mg141 (52–327)104 (41–239)< 0.001
 Simva/Eze 10/10 mg123 (48–237)94 (41–174)< 0.001
HDL cholesterol, mg/dl
 Simva 40 mg58 ± 1359 ± 14ns
 Rosuva 10 mg61 ± 1363 ± 14ns
 Simva/Eze 10/10 mg60 ± 1261 ± 12ns
ApoA-I, mg/dl
 Simva 40 mg155 ± 25159 ± 27ns
 Rosuva 10 mg156 ± 26157 ± 35ns
 Simva/Eze 10/10 mg163 ± 28166 ± 26ns
ApoB, mg/dl
 Simva 40 mg110 ± 2072 ± 19< 0.001
 Rosuva 10 mg124 ± 4075 ± 23< 0.001
 Simva/Eze 10/10 mg115 ± 2570 ± 14< 0.001
ApoE, mg/l
 Simva 40 mg45 ± 1137 ± 10< 0.001
 Rosuva 10 mg42 ± 1135 ± 8< 0.001
 Simva/Eze 10/10 mg45 ± 1235 ± 9< 0.001
Lp(a), mg/dl
 Simva 40 mg12.9 (2.3–89.8)11.7 (2.3–94.1)ns
 Rosuva 10 mg11.7 (2.44–44.2)8.5 (2.44–56)ns
 Simva/Eze 10/10 mg9.6 (2.4–89)9.3 (2.3–63)ns
hs-CRP, mg/l
 Simva 40 mg2.2 (0.4–13)1.7 (0.2–11.2)< 0.001
 Rosuva 10 mg2.6 (0.3–11)2.2 (0.3–5.4)0.04
 Simva/Eze 10/10 mg2.4 (0.5–14.7)2.1 (0.4–10.5)0.04
Table 4.   Body mass index, waist circumference and ALT levels before and after dietary intervention and after 12 weeks of treatment
 PreinterventionAfter 12 weeks of dietary intervention (baseline)After 12 weeks of drug treatmentp
  1. *All values are expressed as mean ± SD except for ALT which is expressed as median (range).

  2. BMI, body mass index; ALT, alanine aminotranferase; Rosuva, rosuvastatin; Simva/Eze, simvastatin/ezetimibe; Simva, simvastatin.

BMI, kg/m2
 Simva 40 mg29 ± 1129 ± 829 ± 8ns
 Rosuva 10 mg29 ± 1029 ± 929 ± 9ns
 Simva/Eze 10/10 mg29 ± 929 ± 829 ± 8ns
Waist circumference, cm
 Simva 40 mg99 ± 1099 ± 1099 ± 10ns
 Rosuva 10 mg99 ± 1099 ± 1099 ± 10ns
 Simva/Eze 10/10 mg98 ± 1097 ± 1097 ± 10ns
ALT levels
 Simva 40 mg24 (9–39)24 (9–39)24 (9–39)ns
 Rosuva 10 mg23 (7–35)23 (7–35)23 (7–35)ns
 Simva/Eze 10/10 mg24 (8–39)24 (8–39)24 (8–39)ns

At week 12, all three treatment regimens were associated with significant increases in HOMA-IR (p < 0.05 compared with baseline) (Table 2). After correcting for baseline values, no significant difference was observed between groups.

Fasting insulin levels were significantly increased in the simvastatin, rosuvastatin and ezetimibe/simvastatin group (p < 0.05 vs. baseline in all groups, Table 2). After correcting for baseline values, no significant difference between groups was found.

Homeostasis model assessment of β-cell function, HbA1c and FPG levels did not change significantly in any of the three groups (Table 2).

The changes in HOMA-IR did not correlate with baseline HOMA-IR, age, gender, waist circumference, BMI, hsCRP, lipid or apolipoprotein levels in any of the groups. In addition, there was no correlation between changes in HOMA-IR and changes in lipids, apolipoproteins or hsCRP in any of the groups.

In a subgroup analysis in patients with IFG (n = 50), treatment with rosuvastatin 10 mg, simvastatin 40 mg or the combination of simvastatin 10 mg with ezetimibe 10 mg showed a non-significant trend towards an increase in HOMA-IR without any difference among groups (data not shown).

At the end of the 12-week treatment period, levels of TC, LDL-C, TGs, apoB and apoE were significantly reduced in all groups (p < 0.001 vs. baseline in all groups). HDL-C, apoA-I and Lp(a) levels were not significantly altered in any of the three groups (Table 3). There was no significant difference between the three groups.

All three treatment regimens were associated with significant reduction in serum hsCRP levels. There was no significant difference between the three groups (Table 3).

As outlined in study protocol, the 153 patients who were randomised to lipid-lowering treatment had participated in a 12-week dietary intervention before drug therapy commence. No significant change in BMI, waist circumference and serum ALT levels (a marker of liver fat content) was noted when preintervention, baseline pretreatment and post-treatment values were compared (Table 4).

Compliance and tolerability

None of the participants dropped out. Compliance rate was > 80% in all patients. All regimens were well tolerated during the study. No patient in any group had liver enzyme elevation > 3-fold ULN or CK > 10-fold ULN. No patient complained of muscle aches or pain. There was no difference in compliance between groups.

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 non-diabetic 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 β 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 β-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 ΗΟΜΑ-ΙR 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.

Conclusion

Simvastatin 40 mg, rosuvastatin 10 mg and simvastatin/ezetimibe 10/10 mg are associated with similar adverse effects on insulin resistance.

Ancillary