Studies have reported an increased risk of developing diabetes in subjects receiving statins versus placebo. Our purpose was to compare the effects of maximum doses of rosuvastatin and atorvastatin on the plasma levels of the insulin, glycated albumin, adiponectin, and C-reactive protein compared to baseline in hyperlipidemic patients. We studied 252 hyperlipidemic men and women who had been randomized to receive atorvastatin 80 mg/day or rosuvastatin 40 mg/day during a 6-week period. Atorvastatin and rosuvastatin were both highly effective in lowering the low-density lipoprotein cholesterol and triglyceride levels, with rosuvastatin more effective than atorvastatin in increasing high-density lipoprotein cholesterol. Atorvastatin and rosuvastatin at the maximum dosage both significantly (p <0.05) increased the median insulin levels by 5.2% and 8.7%, respectively, from baseline. However, only atorvastatin increased the glycated albumin levels from baseline (+0.8% for atorvastatin vs −0.7% for rosuvastatin, p = 0.002). Both atorvastatin and rosuvastatin caused significant (p <0.001) and similar median reductions in the C-reactive protein level of −40% and −26% compared to the baseline values. However, no statistically significant difference was found between the 2 groups in the adiponectin changes from baseline (−1.5% vs −4.9%, p = 0.15). In conclusion, our data have indicated that the maximum dosage of atorvastatin or rosuvastatin therapy significantly lower C-reactive protein levels but also moderately increase insulin levels.
Despite the beneficial effects of atorvastatin and rosuvastatin on lipoprotein cholesterol and C-reactive protein (CRP) levels, concerns exist regarding the effects of these statins on glucose homeostasis. In a substudy of the Pravastatin or Atorvastatin Evaluation in Myocardial Infarction (PROVE-IT), the patients with a baseline hemoglobin A1c (HbA1c) <6% who had received atorvastatin (80 mg/day) had a greater risk of developing HbA1c >6% than the patients who had received pravastatin (40 mg/day). In the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), a 25% greater incidence of physician-reported diabetes was noted in subjects receiving rosuvastatin (20 mg/day) than in those receiving placebo. An increase in HbA1c was also observed in those taking rosuvastatin. More recently, a meta-analysis by Sattar et al confirmed that statins do increase the risk of developing type 2 diabetes. The present study compared the effects of maximum doses of atorvastatin and rosuvastatin on insulin, glycated albumin (GA), and adiponectin (ADN) levels, measures of glucose homeostasis, as well as CRP levels using serum samples from the Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR) study. This study was performed to determine whether maximum statin therapy has an effect on glucose homeostasis because of the data from large statin trials reporting an increased risk of developing diabetes mellitus in those receiving statins versus placebo.
Methods
The details of the design and conduct of the STELLAR study and of the patient population have been previously published. It was an open-label, randomized, parallel group study of hypercholesterolemic patients conducted at 182 United States centers. The primary objective was to compare the efficacy of rosuvastatin in the reduction of low-density lipoprotein (LDL) cholesterol with other statins across the dose ranges. The secondary objectives included a comparison of the effects of the statins on other lipoprotein parameters such as high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I and B, and lipid ratios. Men and nonpregnant women (adults aged ≥18 years) with hypercholesterolemia were asked to follow a National Cholesterol Education Program Step 1 diet for 6 weeks. Those who were compliant with the diet and had fasting calculated LDL cholesterol levels ≥160 mg/dl (4.1 mmol/L) and <250 mg/dl (6.5 mmol/L) and triglycerides <400 mg/dl (4.5 mmol/L) were randomized to the different statin doses, as described. The blood samples were collected on ≥3 occasions before randomization and after 4 and 6 weeks of treatment and sent to a central laboratory (Medical Research International, Highland Heights, Kentucky) for the measurement of lipid and lipoprotein parameters that included total cholesterol, triglycerides, calculated LDL cholesterol, HDL cholesterol, apolipoprotein A-I and apolipoprotein B measurements, as previously described. The serum samples were stored at −80°C at Medical Research International. All subjects provided informed consent to participate in the present study and to have their blood samples used for the analysis of lipoproteins and other cardiovascular risk markers. Multiple human investigational review boards approved the protocol.
For the present substudy, available serum samples that had never been thawed and had been frozen at −80°C, corresponding to the baseline (week 0) and 6-week points of the atorvastatin 80 mg/day and rosuvastatin 40 mg/day arms of the main study were sent on dry ice to the Lipid Metabolism Laboratory (Tufts University, Boston, Massachusetts). A total of 158 and 167 patients were randomized to the rosuvastatin 40 mg/day and atorvastatin 80 mg/day groups of the STELLAR study, and 152 and 160 patients had data recorded at baseline and after 6 weeks of treatment, respectively. Archived serum samples corresponding to the randomization and 6-week points were available for the present study for 135 (89%) and 137 (86%) of these patients. These were the serum samples that had been frozen at −80°C and had been obtained after an overnight fast at the baseline of medication use and after 6 weeks of therapy with either atorvastatin 80 mg/day or rosuvastatin 40 mg/day.
The direct LDL cholesterol and HDL cholesterol levels were measured using kits obtained from Roche Diagnostics (Indianapolis, Indiana), and small dense LDL cholesterol was measured using kits provided by Denka Seiken (Tokyo, Japan), as previously described. Our laboratory has participated in the Centers for Disease Control, National Heart, Lung, and Blood Institutes lipid standardization program (Atlanta, Georgia). GA was measured using kits obtained from Asahi-Kasei Pharma (Tokyo, Japan), as previously described. Adiponectin was measured using a latex particle-enhanced immunoturbidometric assay, and insulin was measured using a latex immunoassay (both assays obtained from Otsuka Pharmaceutical, Tokyo, Japan). The characteristics of these assays have been previously described. CRP was measured using a high-sensitivity immunoassay obtained from Wako Diagnostics (Richmond, Virginia). All assays had a between run and within run coefficient of variation of <5%.
The statistical analysis was performed using the Statistical Package for Social Sciences, for Windows software (SAS Institute, Cary, North Carolina). All continuous variables were checked for their distributions. The results are expressed as the mean ± SD if they were normally distributed or as the median and interquartile range if they were nonlinearly distributed. The changes in all parameters from baseline and by treatment arm were compared using Student’s t test, Wilcoxon signed ranks test, or the Mann-Whitney U test, according to their distributions. p Values of <0.05 were considered statistically significant. A total of 13 patients (7 in the rosuvastatin and 6 in the atorvastatin arm) who had a high GA level (GA >16.5%, consistent with diabetes) were excluded from the analysis of glucose homeostasis and inflammatory markers (see Table 1 ) because of the possible interference in insulin level interpretation and greater prevalence of patients with diabetes in the rosuvastatin group at baseline. We calculated that 68 subjects/group would provide 80% power with an α of 0.05 for detecting a 25% difference in insulin level between the 2 treatment groups.
| Variable | Atorvastatin 80 mg/day | Rosuvastatin 40 mg/day | ||
|---|---|---|---|---|
| 6-wk Level | p Value ⁎ | 6-wk Level | p Value ⁎ | |
| Insulin (μIU/ml) † | 7.5 (2.6–35.8) | 0.007 | 8.6 (2.5–25.5) | 0.026 |
| Adiponectin (μg/ml) † | 11.0 (4.0–35.9) | 0.262 | 9.8 (2.4–60.2) | 0.005 |
| Glycated albumin (%) ‡ | 13.4 (10.6–18.7) | 0.53 | 13.1 (10.1–16.4) | 0.0017 |
| C-reactive protein (mg/L) ‡ | 1.1 (0.1–33.5) | <0.001 | 1.6 (0.1–25.7) | <0.001 |
⁎ p Values were based on an analysis comparing the changes from baseline.
† Number of subjects analyzed was 72 for both atorvastatin and rosuvastatin.
‡ Number of subjects analyzed was 129 for atorvastatin and 130 for rosuvastatin groups.
Results
The subject characteristics and lipids and other biochemical levels at baseline are listed in Table 2 . The 2 groups of patients were well-matched according to gender, age, and disease characteristics, except that those taking rosuvastatin had a greater prevalence of diabetes. The 2 groups were also well-matched with regard to the baseline levels of lipoproteins, except that the subjects randomized to the rosuvastatin group had significantly greater levels of non–HDL cholesterol, calculated LDL cholesterol, direct LDL cholesterol, and small dense LDL cholesterol, although these differences were not large between the 2 groups at baseline. The sample sizes presented in our tabular data represent the number of patients who both completed treatment and had serum samples available for the measurements (135 in the atorvastatin group and 137 in the rosuvastatin group). However, 76 samples in both the atorvastatin and rosuvastatin groups were available for insulin and ADN measurement. The samples not measured had insufficient serum available for the analysis. No statistically significant difference was found between the mean age and baseline median GA levels between those with missing data and those with samples available for measurement in both treatment groups ( Table 2 ).
| Variable | Atorvastatin 80 mg | Rosuvastatin 40 mg | ||
|---|---|---|---|---|
| Total Subjects (n = 135) | Those With Samples Available for Analysis (n = 76) | Total Subjects (n = 137) | Those With Samples Available for Analysis (n = 76) | |
| Gender | ||||
| Men | 67 | 38 | 71 | 39 |
| Women | 68 | 38 | 66 | 37 |
| Age (years) | 58.6 ± 11.0 | 59.6 ± 10.1 | 55.9 ± 12.7 | 55.9 ± 13.5 |
| Body mass index (kg/m 2 ) | 29.4 ± 6.2 | NA | 29.5 ± 12.6 | NA |
| Coronary heart disease | 20.4% | NA | 19.6% | NA |
| Diabetes mellitus | 5.4% | 5.3% | 9.5% ⁎ | 5.3% |
| Total cholesterol (mg/dl) | 278.3 ± 30.7 | 275.9 ± 32.2 | 283.2 ± 26.7 | 284.7 ± 26.8 |
| Triglycerides (mg/dl) | 178.1 ± 75.1 | 168.7 ± 76.2 | 183.2 ± 70.8 | 175.1 ± 69.7 |
| High-density lipoprotein cholesterol (mg/dl) | 52.3 ± 14.1 | 53.1 ± 13.7 | 50.1 ± 12.6 | 52.9 ± 11.7 |
| Total cholesterol / high-density lipoprotein cholesterol ratio | 5.7 ± 1.5 | 5.5 ± 1.3 | 6.0 ± 1.4 | 6.0 ± 1.1 |
| Non–high-density lipoprotein cholesterol (mg/dl) | 226.0 ± 31.4 | 223.1 ± 31.0 | 233.2 ± 25.5 ⁎ | 231.8 ± 23.9 ⁎ |
| Calculated low-density lipoprotein (mg/dl) | 190.7 ± 25.7 | 189.4 ± 26.7 | 196.7 ± 24.0 ⁎ | 196.8 ± 25.4 |
| Direct low-density lipoprotein cholesterol (mg/dl) | 197.8 ± 27.2 | 198.1 ± 27.5 | 204.4 ± 27.1 ⁎ | 206.1 ± 27.5 |
| Small dense low-density lipoprotein cholesterol (mg/dl) | 63.2 ± 25.4 | 62.5 ± 23.4 | 71.6 ± 29.9 ⁎ | 72.9 ± 28.8 ⁎ |
| C-reactive protein (mg/L) | 1.8 (0.2–23.8) | 1.9 (0.2–23.8) | 2.3 (0.2–60.6) | 2.3 (0.2–10.4) |
| Glycated albumin (%) | 13.4 (7.2–22.6) | 13.4 (10.4–22.6) | 13.3 (9.8–18.1) | 13.2 (9.8–17.4) |
| Insulin (μIU/ml) | 7.1 (0.9–22.3) | 7.9 (2.3–32.0) | ||
| Adiponectin (μg/ml) | 11.9 (3.9–40.4) | 11.0 (2.5–64.8) | ||
Both statins significantly increased the insulin levels from baseline ( Table 1 ). Rosuvastatin slightly decreased GA from baseline, with no significant change observed with atorvastatin treatment. ADN levels decreased from baseline with both treatments, with a significant change in the rosuvastatin group. Both drugs decreased the CRP levels significantly from baseline. An analysis was also performed of all subjects, including those with a high GA level (GA >16.5%); however, the difference remained statistically significant in all parameters mentioned.
It was evident that both atorvastatin and rosuvastatin caused significant and similar decreases in total cholesterol and triglycerides ( Table 3 ); however, the rosuvastatin 40 mg/day group had greater reductions in the total cholesterol/HDL ratio, non-HDL cholesterol, LDL cholesterol, and small dense LDL cholesterol levels. In addition, rosuvastatin was also more effective in increasing the HDL cholesterol level. Both statins caused similar reductions in CRP. Although both statins increased the insulin level significantly from baseline, no significant difference was seen between the 2 groups. The GA levels increased with atorvastatin treatment but not with rosuvastatin treatment. No significant difference was seen between the 2 groups in ADN changes from baseline. The variability in the responses to the statins (percentage of change from baseline) in terms of the changes in insulin, ADN, GA, and CRP are shown in Figure 1 . As can clearly be seen, the variability in the response was very wide, especially for the statin-induced changes in insulin and CRP.
