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Joslin Diabetes Center (P.A.E., E.T., E.S.H.) and Microcirculation Laboratory (A.C., L.K., A.V.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston Massachusetts 02215
Address all correspondence and requests for reprints to: Aristidis Veves, M.D., Microcirculation Laboratory, Palmer 317, Beth Israel Deaconess Medical Center, West Campus, One Deaconess Road, Boston, Massachusetts 02215. E-mail: aveves{at}bidmc.harvard.edu.
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Abstract |
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[median (25–75 percentile), 2.6 pg/ml (1.8–4.1 pg/ml) at exit visit vs. 4.4 pg/ml (3.6–6.0 pg/ml) at baseline; P < 0.05] in the atorvastatin-treated patients, whereas in the diabetes group, a decrease in endothelin-1 (mean ± SD, 0.97 ± 0.29 pg/ml at exit visit vs. 1.19 ± 0.42 pg/ml at baseline; P < 0.05) and plasminogen activator inhibitor-1 [median (25–75 percentile), 18 ng/ml (9–24 ng/ml) at exit visit vs. 27 ng/ml (7–41 ng/ml) at baseline; P < 0.05] were observed. We conclude that atorvastatin improves endothelial function and decreases levels of markers of endothelial activation and inflammation. |
Introduction |
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Statins have been shown to lower serum cholesterol levels markedly and reduce cardiovascular morbidity and mortality (7). Although it was initially thought that the reduction in cardiovascular disease was solely related to their lipid-lowering capacity, over the last few years, it has been recognized that statins may additionally act through mechanisms that are independent of low-density lipoprotein (LDL) cholesterol lowering to provide a 30% relative risk reduction of major coronary events (8). Several such mechanisms have been proposed, including the up-regulation of endothelial nitric oxide synthase expression and nitric oxide production, antiinflammatory action and effects on thrombosis, and favorable effects on plaque architecture and stability (9, 10, 11). Thus, it is currently accepted that statins have pleiotropic properties that may contribute to the observed reduction in cardiovascular disease (12).
Direct action on the endothelial cell has emerged as one of the most prominent mechanisms through which statins may exert their beneficial effects (13, 14). Therefore, if this hypothesis is correct, it would be expected that treatment with statins should improve the impaired endothelial function when it is impaired in conditions such as diabetes or the prediabetic stage, even under conditions of normolipidemia. The main objective of this study was to study the effect of atorvastatin, one of the most powerful statins in providing total cholesterol, LDL, and triglyceride reduction, on the endothelial function of the micro- and macrocirculation. To this end, we have conducted a double-blind, randomized, placebo-controlled clinical trial that included subjects with impaired endothelial function divided into one group of healthy subjects at risk of developing diabetes and one group of patients with type 1 or 2 diabetes.
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Subjects and Methods |
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A total of 77 subjects were included in the study. Subjects were enrolled if they were between the ages of 21 and 80 yr and at risk for type 2 diabetes (either having a first-degree relative with type 2 diabetes and normal glucose tolerance or impaired glucose tolerance defined as a 2-h blood glucose value between 140–199 mg/dl during a 75-g oral glucose tolerance test) or had type 1 or type 2 diabetes. Diabetes was defined according to the recommendations of the American Diabetes Association Expert Committee on the Classification and Diagnosis of Diabetes (15).
To avoid confounding factors known to affect endothelial function and/or glucose metabolism, the following exclusion criteria were applied: treatment with lipid-lowering drugs during the previous 3 months, cardiac arrhythmia, congestive heart failure, uncontrolled hypertension, recent stroke, chronic renal disease, macroalbuminuria (expressed as albumin to creatinine ratio > 300 µg/mg), severe dyslipidemia (triglycerides > 600 mg/dl or cholesterol > 300 mg/dl), or any other serious chronic disease requiring active treatment. Subjects were also excluded if they were on any of the following medications: glucocorticoids, antineoplastic agents, psychoactive agents, and bronchodilators.
The protocol was approved by the ethics committee or institutional review board at each center, and all participants gave written informed consent. Volunteers for the study were recruited through local advertisement at the Joslin Diabetes Center and the Beth Israel Deaconess Medical Center in Boston.
Methods
Volunteers attended the Joslin Diabetes Center Clinical Research Center to undergo the clinical and laboratory evaluations. A general physical examination was performed by a study physician. Subjects were studied at all visits after an overnight fast. Participants were asked not to take their diabetes medications (sulfonylureas or metformin) for 12 h before any of the studies, and those participants taking insulin were asked to omit the rapid-acting insulin the morning of each visit.
Plasma glucose, total serum cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, liver function tests, electrolytes, blood urea nitrogen, and creatinine were measured using the Synchron CX analyzer (Beckman/Coulter, Brea, CA). Routine urinalysis was also performed. The glycosylated hemoglobin (normal range, 4–6%) was determined in whole blood using ion-exchange HPLC (Tosoh 2.2, Tokyo, Japan). Soluble intercellular adhesion molecule [coefficient of variation (cv), 4.4%], soluble vascular cell adhesion molecule (cv, 5.0%), and endothelin-1 (cv, 4.4%) were measured in plasma by an ELISA method (R&D Systems, Minneapolis, MN). TNF (cv, 4.7%) and high-sensitivity C-reactive protein (CRP; cv, 5.1%) were measured by chemiluminescent immunoassay. Von Willebrand factor (cv, 6.1%), plasma activator inhibitor (PAI; cv, 6.0%) antigen, and tissue plasminogen activator (tPA; cv, 4.5%) antigen were also measured by an ELISA method (Diagnostica Stago, Parsippany, NJ).
Vascular reactivity tests
All eligible participants returned for a second visit to the Microcirculation Laboratory at the Beth Israel Deaconess Medical Center to undergo the vascular reactivity tests. All measurements were performed in the morning, while the subjects were in a fasting state. The investigators who performed the vascular reactivity measurements were blinded to the medical history of the subjects. These studies were carried out in a temperature-controlled room (24–26 C) and after a 30-min acclimatization period.
The vascular reactivity of the forearm skin microcirculation was evaluated by Laser Doppler perfusion imaging measurements before and after the iontophoresis of acetylcholine chloride (endothelium-dependent vasodilation) and sodium nitroprusside (endothelium-independent vasodilation), as previously described (16). The reproducibility of the technique has been previously reported by our group. The cv of the baseline measurement was 14.1%, and during maximal hyperemic response after the iontophoresis, it was 13.7% (17).
To assess the endothelium-dependent reactivity in the macrocirculation, the flow-mediated dilation (FMD) of the brachial artery was measured by using a high-resolution ultrasound with a 10.0-MHz linear array transducer and an HDI Ultramark 9 System (Advanced Technology Laboratories, Bothel, WA). All measurements were in accordance with recently published guidelines (18). Reactive hyperemia is produced by inflating a pneumatic tourniquet distally to the brachial artery to 50 mm Hg above the systolic pressure for 5 min and then deflating it. Endothelium-independent vasodilation in the macrocirculation was assessed by studying brachial artery diameter changes 5 min after the administration of 400 µg of sublingual nitroglycerine (nitroglycerine-induced dilation). This test was performed 15 min after the reactive hyperemia test and after obtaining a new baseline reading.
After the baseline clinical and laboratory evaluations, participants in all three groups were randomized to either 20 mg atorvastatin treatment or corresponding placebo. The randomization procedure was carried out in a double-blind fashion, and the codes were kept masked until the end of the study.
Participants were asked to return for the exit visit after a 12-wk treatment period. The diabetic patients were also asked to continue with their same diabetes medications and dosages and were encouraged to continue with their usual meal plan and physical activity level. In case problems with diabetes control were encountered, any modification to the diabetes management was recorded. During the exit visit, blood tests for glycosylated hemoglobin, glucose, biochemical markers of inflammation, and endothelial function were taken, and the vascular reactivity in the micro- and macrocirculation was measured.
Data analysis
The Minitab statistical package (Minitab Inc., State College, PA) for personal computers was used for the statistical analysis. A two-tailed comparison was assumed. The analyses were performed using a paired t test for parametrically distributed data and the Wilcoxon matched-pair signed rank test for nonparametrically distributed data to compare baseline data and changes in all variables at the end of the study within each group. The t test was used to compare the baseline characteristics between those receiving active treatment and those receiving placebo in all groups. Correlation between variables was tested using both univariate and multivariate analyses (Pearson’s correlation and Spearman correlation analysis for parametrically and nonparametrically distributed data and analysis and multiple stepwise regression analysis). The results are presented as mean ± SD and median (25–75 percentile).
Corrections for multiple comparisons
We tested whether the number of significant results for a single group was consistent with chance or not. There are 14 separate comparisons (see Tables 4
and 5) for each of the four groups (at risk of type 2 diabetes and diabetic patients, treated or placebo). With 14 significance tests and a nominal two-sided = 0.05, one would expect 0.9 significant results per group (0.7 = 14 x 0.05), and, if results for different variables are independent, then the number of significant tests would follow a Poisson distribution. We observed no significant results in placebo-treated, at-risk patients and one significant result in placebo-treated diabetic subjects, both of which are consistent with chance. In contrast, in atorvastatin-treated patients in both groups we observed three significant results, suggesting that these results are real findings.
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Results |
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. There were no differences between the groups in age, gender, body mass index, blood pressure, and lipid levels. Results of the baseline measurements of vascular reactivity and biochemical markers of endothelial function are given in Table 2. All vascular reactivity measurements were similar in the two groups, but the vascular cell adhesion molecule, endothelin-1, and von Willebrand Factor levels were higher in the diabetic group.
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and 4
). Thirty subjects (81%) at risk of developing diabetes and 37 diabetic patients (93%) completed the study. There were no differences between those who did not complete the study and those who did.
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Atorvastatin-treated patients showed a significant reduction in total cholesterol, LDL, and triglycerides, whereas no changes were observed in HDL (Table 3). No changes were observed in weight, systolic and diastolic blood pressure, and fasting glucose. Finally, no changes were observed in any parameter in the placebo-treated subjects.
The main results on the endothelium-dependent and -independent vasodilatory responses in the macro- and microcirculation are shown in Table 4. A significant improvement in the FMD in the brachial artery diameter was found in the atorvastatin-treated patients after 3 months of treatment (P < 0.05). In contrast, no significant changes in the brachial artery dilation were seen in response to nitroglycerin. No significant changes were seen in the endothelium-dependent and -independent responses in the skin microcirculation.
A reduction in CRP and TNF levels was observed in the atorvastatin-treated patients (P < 0.05, Table 5). No changes were found in any of the biochemical endothelial measurements in the placebo-treated group. No correlations were found between the FMD changes and changes in total cholesterol and LDL, triglycerides, CRP, and TNF (Figs. 1 and 2).
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Atorvastatin-treated patients showed a significant reduction in total cholesterol and LDL and a decrease in HDL (Table 3). Of interest, the placebo group also had a small but statistically significant reduction in total and LDL cholesterol. No changes were observed in weight, systolic and diastolic blood pressure, and glycemic control in either of the two groups.
The FMD improved in the atorvastatin-treated patients but failed to reach statistical significance (P = 0.07, Table 4). As with the placebo group, no changes were observed in the nitroglycerine-induced dilation and microvascular reactivity measurements. No changes in the vascular reactivity were observed in the placebo-treated group.
A significant reduction was observed in the endothelin-1 and PAI-1 levels in the atorvastatin group (Table 5). In addition, a significant reduction was observed in the tPA in both the atorvastatin and placebo groups. No correlations were found between the FMD changes and changes in total cholesterol, LDL, endothelin 1, PAI-1, and tPA.
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Discussion |
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levels in the subjects at risk of developing diabetes and the endothelin-1 and PAI-1 levels in the diabetic patients. Treatment with statins improved the endothelial function in patients with coronary artery disease and in postmenopausal normocholesterolemic women (19, 20). Regarding the effect of statins in diabetes, the data are conflicting, with the majority of the published studies suggesting no effect of treatment with statins on endothelial function (21, 22, 23, 24). However, two recent studies have reported a beneficial effect of statins on the endothelial function in type 2 diabetic patients. The first one used simvastatin 20–40 mg and had a target of LDL less than 80 mg, whereas the second study used a regimen similar to the present study, atorvastatin 20 mg daily (25, 26). One common characteristic of the above studies is that they included subjects with dyslipidemia. Atorvastatin 40 mg once daily improved the flow-mediated vasodilation in patients with type 1 diabetes (27). Cerivastatin was also shown to improve endothelial function in elderly diabetic patients within 3 d without affecting the lipid profiles (28). In addition to the reported effects on the endothelial function, treatment with atorvastatin decreased the carotid intima medial thickness, a validated surrogate cardiovascular end point, in patients with hyperlipidemia (29).
In the present study, we found a positive effect of atorvastatin on the endothelial function of healthy subjects at risk of developing type 2 diabetes, a population that is known to have impaired endothelial function (3, 4). Their mean baseline lipid levels were similar to those that are currently recommended as targets for successful treatment. In addition, concentrations of total cholesterol and LDL attained in the atorvastatin-treated subjects were well below the currently recommended levels. Thus, to our knowledge, this is the first study to show a positive effect of atorvastatin on the endothelial function of subjects at risk of developing diabetes with no dyslipidemia.
A similar but nonsignificant improvement was also found in the endothelial function of the diabetic patients. The main reason for this failure is that, on the basis of preliminary reports, we anticipated a considerably higher improvement of the endothelial function (19, 28). Therefore, we believe that this marginal failure to reach statistical significance is likely to represent a type 2 statistical error and that the observed improvement is real. It should also be emphasized that, in contrast to previous studies, dyslipidemia was not an inclusion criterion in the present study, and therefore, as with the at-risk group, the baseline mean cholesterol levels were close to the currently recommended therapeutic targets, whereas the atorvastatin-treated patients reached much lower levels. Therefore, these results indicate that treatment with statins can be beneficial even in the presence of normal plasma total and LDL cholesterol concentrations.
Treatment with atorvastatin did not result in any changes in the microcirculation endothelium-dependent and -independent vasodilation in either studied group, which is a finding that is in agreement with previous studies (30). Previous studies from our unit and elsewhere have shown that both these measurements are impaired in subjects at risk of developing diabetes and diabetic patients (31). Although the reasons for this difference in the response to atorvastatin treatment in the micro- and macrocirculation are not clear, it should be remembered that atherosclerosis is a process that is confined in the macrocirculation and is influenced by factors such as hyperlipidemia and insulin resistance. In contrast, the microcirculation is mainly influenced by hyperglycemia, and this is best seen by the fact that clinical microvascular complications, such as retinopathy, neuropathy, and nephropathy, are not present in the prediabetic stage. Further studies will be required to examine whether other therapeutic interventions, such as treatment with angiotensin-converting enzyme inhibitors, may be better candidates in reversing microvascular abnormalities.
Previous studies have shown that statins can reduce CRP levels in nondiabetic subjects with dyslipidemia and diabetic patients in a relatively short period of time (32, 33, 34). In the present study, a 50% reduction in CRP levels was observed in the at-risk group. In the same group, a significant reduction was also observed in TNF levels. Previous in vitro studies have suggested that statin treatment can reduce the TNF production by human monocytes stimulated by oxidized LDL (35). This is the first study to indicate that treatment with a statin can reduce TNF levels in humans. Further studies will be needed to further explore these findings.
Endothelin-1 levels were higher in the diabetic group and were reduced in the atorvastatin-treated patients. Previous in vitro studies have shown that statins reduce the expression of endothelin-1 in endothelial cells (36, 37). Our findings are consistent with these studies and are the first to observe such en effect in humans. We believe that endothelin levels did not change in the at-risk group because initial concentrations were not as high as in the diabetic patients, and therefore, a possible beneficial effect could not be seen.
Atorvastatin has also been shown to reduce the expression of PAI-1 in human vascular smooth muscle and endothelial cells (38, 39). In the present study, atorvastatin treatment had a beneficial effect in both groups, but a statistical significance was reached only in the diabetic patients. The main reason for not reaching significance in the at-risk group is related to the small number of tested subjects and the considerable variation in the PAI-1 levels. Finally, a reduction in the tPA was observed in both the actively treated and placebo-treated diabetic patients. The reduction in PAI-1 levels may be the main factor in the atorvastatin-treated patients, but the reasons in the placebo group are not clear. The fact that a small but significant reduction in total and LDL cholesterol levels was also observed in the diabetic placebo-treated patients further indicates this possibility.
Statins are currently thought to have pleiotropic effects that are independent of their lipid-lowering function (40). However, previous studies have shown an association between the cholesterol changes and endothelial function. Thus, in one study, drastic reduction of LDL cholesterol by apheresis, which resulted in a postapheresis mean LDL of 33 mg/dl, was accompanied by a considerable improvement of the endothelial function while significant correlations where found between LDL levels and endothelial function (41). In addition, other studies have shown that isolated low HDL levels are associated with endothelial dysfunction, which is completely restored to normal levels by a rapid increase in HDL (42). Low HDL levels are thought to cause reduced nitric oxide bioavailability because of reduced endothelial nitric oxide synthase expression and/or activity (43).
In this study, no relationship was found between the achieved total and LDL cholesterol reduction and the changes in the FMD or the biochemical markers of endothelial dysfunction. In addition, a reduction was noted in the HDL cholesterol in the atorvastatin-treated diabetic patients despite an increase in the FMD. The reasons for the discrepancy between our study and the previous ones are not clear but may be related to the fact that we included patients without severe dyslipidemia and that the achieved changes in the HDL and LDL levels were as extreme as in the previous studies. In addition, it should be emphasized that the main aim of this study was to evaluate the effect of atorvastatin on vascular function, and it lacked the statistical power that would allow it to dissect the mechanisms that are responsible for this beneficial effect. Therefore, it is possible that the changes in LDL and HDL levels may have influenced our results in the present study; for example, the improvement of the FMD in the diabetic group might have been more dramatic if the reduction in the HDL was not present. Further trials that will be focused on these issues will be required before definite conclusions are reached.
The present study has its limitations. The main limitation is that this is a small study that focused on showing a proof of principle, and as such, it did not include a large cohort of subjects that could allow full statistical analysis. Thus, the study was mainly powered to detect changes in the FMD because there was no information available at that time regarding the effect of atorvastatin on biochemical markers of endothelial dysfunction. This is probably the main reason that discrepancies were found in the response of the various endothelial markers (such as TNF, CRP, and PAI-1) in the at-risk and diabetic patients who were treated with atorvastatin. Further studies will be required to further explore the findings of the present study before solid conclusions can be reached.
Another limitation may be the fact that, in group 1, we included healthy subjects with parental history of type 2 diabetes and subjects with impaired glucose tolerance, whereas in group 2, we included both type 1 and type 2 diabetic patients. However, because previous studies have shown similar impairment in the endothelial function of subjects with parental history of type 2 diabetes and subjects with impaired glucose tolerance or type 1 and 2 diabetic patients, we believe that our inclusion criteria did not affect the study outcomes (1, 2, 3, 4). We believe that the most important factor was to have the at-risk and diabetic groups being matched for age, gender, and lipidemia, and this was fully achieved.
In conclusion, in the present study, we have shown that atorvastatin improves the endothelial function of the macrocirculation and decreases levels of markers of endothelial activation in diabetic patients and in subjects at risk of developing type 2 diabetes.
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Footnotes |
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Abbreviations: CRP, C-reactive protein; cv, coefficient of variation; FMD, flow-mediated dilation; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PAI, plasma activator inhibitor; tPA, tissue plasminogen activator.
Received June 30, 2003.
Accepted October 22, 2003.
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References |
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and NF
B expression by pravastatin in response to lipoproteins in human monocytes in vitro. Pharmacol Res 45:147–154[CrossRef][Medline]
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