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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0453
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 8 3136-3140
Copyright © 2007 by The Endocrine Society

Concomitant Reduction of Low-Density Lipoprotein-Cholesterol and Biomarkers of Inflammation with Low-Dose Simvastatin Therapy in Patients with Type 1 Diabetes

Ishwarlal Jialal, Eric Miguelino, Steven C. Griffen and Sridevi Devaraj

University of California, Davis, Medical Center, Sacramento, California 95817; and Veterans Affairs Medical Center, Mather, California 95655

Address all correspondence and requests for reprints to: I. Jialal, M.D., Ph.D., Director, Laboratory for Atherosclerosis and Metabolic Research, 4635 II Avenue, Res 1 Building, Room 3000, University of California, Davis, Medical Center, Sacramento, California 95817. E-mail: ishwarlal.jialal{at}ucdmc.ucdavis.edu.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Cardiovascular disease is a major cause of mortality in type 1 diabetes (TIDM). TIDM is a proinflammatory state. Whereas there is consensus on lipid management in type 2 diabetes, there is a lack of data in type 1 diabetes. In addition to benefits on the lipid profile, statin therapy is antiinflammatory.

Objective: There are scant data on statin therapy in T1DM. Thus, we tested the effect of simvastatin, compared with placebo, on biomarkers of inflammation and monocyte function in TIDM patients.

Design: This was a double-blind, randomized, placebo-controlled study of T1DM patients, randomized to placebo or simvastatin, 20 mg/d for 3 months.

Setting: The study was conducted at the University of California, Davis, Medical Center.

Participants: Participants included patients with T1DM.

Methods and Results: Analytes measured at baseline and 3 months included liver function tests, creatinine, hemoglobin AIC, high-sensitivity C-reactive protein, soluble CD40 ligand, monocyte O2–, cytokines, nuclear factor-{kappa}B. Simvastatin therapy resulted in significant reduction in low-density lipoprotein and non-high-density lipoprotein cholesterol, high-sensitivity C-reactive protein (18% reduction, P < 0.001) and soluble CD40 ligand (22% reduction, P < 0.05), compared with placebo. Simvastatin therapy significantly inhibited lipopolysaccharide-activated monocyte release of O2– (P < 0.0005), IL-8 (P < 0.03), and TNF (P < 0.02). Simvastatin therapy significantly inhibited monocyte IL-6 release, compared with baseline (P = 0.02). Simvastatin therapy also significantly reduced monocytic nuclear factor-{kappa}B p65 activity, compared with placebo (P < 0.01).

Conclusions: This study demonstrates that simvastatin (20 mg/d) is safe in T1DM patients and has concomitant benefits on the lipid profile and biomarkers of inflammation. These novel findings could have implications for developing policy guidelines for statin therapy in forestalling vascular complications in young T1DM.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE INCIDENCE OF coronary artery disease (CAD) is approximately 1–2% per year among young, asymptomatic persons with type 1 diabetes mellitus (T1DM). However, by their mid-40s, more than 70% of men and 50% of women with T1DM develop coronary artery calcium, a marker of atherosclerotic plaque burden. CAD is the main cause of death in persons with T1DM. By age 55 yr, 35% of T1DM patients die of CAD in contrast to only 8% of nondiabetic men and 4% of women. Compared with the general population, in T1DM patients, atherosclerosis occurs earlier in life; is more diffuse; and leads to higher case fatality, higher restenosis rates, and shorter survival (1).

Whereas low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels may be more favorable in T1DM patients than nondiabetic controls, T1DM has qualitative abnormalities, such as increased small, dense LDL particles (2). Furthermore, we recently reported that, just as in type 2 diabetes mellitus (T2DM), patients with T1DM are also in a proinflammatory state as evidenced by high plasma levels of C-reactive protein (CRP) and monocyte IL-6, superoxide anion, soluble intercellular adhesion molecule, soluble CD40 ligand (sCD40L), and nitrotyrosine levels (3). Existing clinical data do not adequately address the potential impact of recent improvements in T1DM management on CAD outcomes. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) reduce CAD events in T2DM (4, 5, 6). In the Heart Protection Study, treatment with simvastatin reduced cardiovascular events in T1DM and T2DM, regardless of baseline LDL-cholesterol levels, however the study was not powered to examine effects in T1DM alone (7). It appears that the benefits of statins with regard to cardiovascular disease cannot be attributed only to LDL lowering. Recently several antiatherogenic properties, independent of their LDL-lowering effects, have been attributed to statins such as decrease in CRP, improvement of endothelial function, and decreasing monocyte inflammation (8, 9, 10). Thus, the aim of this study was to examine the effect of simvastatin therapy (20 mg/d) on biomarkers of inflammation and monocyte function in T1DM in a randomized, placebo-controlled, double-blind trial.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Participants and procedures

This study was approved by the Institutional Review Board at University of California, Davis, Medical Center and initiated in the year 2002. After informed consent, type I diabetic patients (onset < 20 yr and on insulin therapy since diagnosis) without clinical macrovascular complications were recruited without restriction to gender, race, or socioeconomic status. T1DM patients with duration of diabetes 1 yr or longer were chosen to avoid the autoimmune and inflammatory response present with the onset of the disease. Patients on Glucophage and/or the thiazolidenediones were excluded because these drugs are antiinflammatory. Other exclusion criteria for the study included the following: mean hemoglobin A1c (HbA1c) over the last year greater than 10%, inflammatory disorders (such as rheumatoid arthritis, systemic lupus erythematosus, etc., or CRP > 10 mg/liter, and/or leukocytosis); abnormal liver function; hypo- or hyperthyroidism; dyslipidemia (total cholesterol > 240 mg/dl and triglycerides > 400 mg/dl) and malabsorption; steroid therapy and vitamin and/or mineral therapy; antiinflammatory drugs except aspirin (81 mg/d) as recommended by the American Diabetes Association (ADA) because this dose is not antiinflammatory (11); pregnancy, smoking, abnormal complete blood count (low hemoglobin, high white blood count, or increased platelets); alcohol consumption more than 1 oz/d; consumption of N-3 polyunsaturated fatty acid capsules more than 1 g/d; and chronic high-intensity exercise. Female subjects were studied in the follicular phase of the menstrual cycle to minimize the effect of the menstrual cycle on cytokines and adhesion molecules.

After history and physical examination, baseline electrocardiograms, ankle-brachial indices by Doppler studies, and sonograms of the carotids for stenoses were undertaken to rule out macrovascular disease. Also, subjects underwent urine tests for evaluation of microalbuminuria and subjects with macroalbuminuria (>300 mg/g creatinine) were excluded. One patient with proliferative retinopathy and two with microalbuminuria were entered into the study.

Fasting blood (45 ml) and 24-h urine were obtained at baseline and 3 months after therapy. After the baseline blood draw, 52 T1DM patients, 20 yr of age or older (n = 26/group) were randomly assigned to placebo or simvastatin 20 mg/d for a period of 3 months. Simvastatin tablets and placebo were provided by Merck Pharmaceuticals (Whitehouse Station, NJ). All subjects were administered an equal number of tablets for effective blinding. Participants were matched for age, ethnicity, and gender. All participants were asked to return at 6 wk to assess liver function. Study participants were asked to adhere to the ADA diet and usual exercise program throughout the study. The subjects were either on Novolog, Humalog, regular insulin, and/or Lantus or on the pump; average insulin dose was 53 ± 14 U/d. Compliance with treatment was determined by counting the remaining pills, periodic telephone conversations, and the lipid profile. Parameters of inflammation and monocyte function were assessed at baseline and after therapy.

A complete blood cell count, plasma lipid and lipoprotein profile, creatinine, liver function tests, blood glucose, glycated hemoglobin, and TSH as well as urinary microalbumin were assayed in the clinical pathology laboratory using standard laboratory techniques.

Plasma high-sensitivity CRP (hsCRP) levels were measured by a high-sensitivity assay on the LxPro (Beckman, Palo Alto, CA). Soluble CD40 ligand levels were measured in plasma by a sandwich ELISA (3). The intra- and interassay coefficients of variation of these assays was less than 6%.

Mononuclear cells were isolated from fasting heparinized blood by Ficoll Hypaque gradient followed by monocyte isolation using magnetic cell sorting by the depletion technique (Miltenyi Biotech, Auburn, CA) as described previously (3). Isolated monocytes were activated using lipopolysaccharide (1 µg/ml for O2– and cytokine and chemokine release for 15 h), and the following functions were studied before and after therapy: O2– release; release of IL-1ß, IL-6, and TNF-{alpha}; and adhesion to human aortic endothelial cells. O2– generation in lipopolysaccharide (LPS)-activated monocytes was measured as the superoxide dismutase-inhibitable reduction of acetylated ferricytochrome C as described previously (3). Results were expressed as nanomoles superoxide per minute per milligram cell protein. The release of the cytokines IL-1ß, IL-6, and TNF-{alpha} and IL-8 in plasma and supernatants of LPS-activated monocytes was assessed using the Becton Dickinson Fluorescence Activated Cell Scan (Becton Dickinson, Franklin Lakes, NJ) array and expressed as nanograms per milligram cell protein. Adhesion of human monocytes to confluent monolayers of human aortic endothelial cell (obtained from Clonetics, Walkersville, MD) was carried out by a fluorescence method as described previously (3). Nuclear factor-{kappa}B (NFKb) p65 activity was assessed in the monocytic cells before and after therapy as described previously (12).

Statistics

After Kruskal-Wallis ANOVA, significant variables were analyzed using Wilcoxon rank sum or paired t tests for nonparametric and parametric data, respectively. Spearman and Pearson’s correlation were performed to assess association between variables.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Baseline characteristics of T1DM patients in the study is provided in Table 1Go. There were no significant differences in any parameters between the two groups at baseline. Simvastatin therapy did not affect liver function tests or cause myopathy. Compared with placebo, simvastatin therapy resulted in a significant reduction in total, LDL and non-HDL cholesterol (P < 0.0001); however, there was no change in HDL cholesterol levels or triglycerides. In 15 of 26 patients, LDL cholesterol was reduced to less than 100 mg/dl. Furthermore, simvastatin therapy did not result in any significant changes in HbA1c (Table 2Go).


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  		TABLE 1. Baseline subject characteristics

 

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  		TABLE 2. Effect of simvastatin therapy on lipid profile and HbA1c

 
With regard to plasma biomarkers of inflammation, simvastatin therapy resulted in significant reduction in hsCRP levels, compared with baseline and placebo (18% reduction, P < 0.001, Table 3Go). Also, simvastatin therapy, compared with placebo, resulted in a significant decrease in sCD40L (22% reduction, P < 0.05, Table 3Go). With regard to plasma cytokines, simvastatin therapy significantly decreased IL-8 levels, but there was no significant change in plasma IL-1, IL-6, and TNF levels, compared with placebo (Table 3Go).


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  		TABLE 3. Effect of simvastatin therapy on plasma cytokines

 
Simvastatin therapy significantly inhibited LPS-activated monocyte release of O2– (56% inhibition, P < 0.0005, Table 4Go), IL-8 (51% reduction, P < 0.03, Table 4Go), and TNF (46% inhibition, P < 0.02, Table 4Go), compared with placebo. Also, there was a significant reduction in monocyte IL-6 release in the simvastatin group, compared with baseline (65%, P = 0.02, Table 4Go). However, there were no significant changes in monocyte IL-1b levels (data not shown). Furthermore, there were no significant changes in adhesion of monocytes to endothelium after simvastatin therapy, compared with placebo (placebo-baseline: 24 ± 19% and post: 29 ± 17%; simvastatin-baseline: 28 ± 14% and post: 25 ± 14%). In addition, simvastatin therapy resulted in a significant reduction in NFKb activity, compared with baseline and placebo (61%, P < 0.01, Table 4Go). Furthermore, responses to simvastatin therapy were similar in patients with HbA1c less than 7% or more than 7% for LDL, hsCRP, monocyte superoxide, IL-8, and TNF.


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  		TABLE 4. Effect of simvastatin therapy on monocyte activity

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Based on the clinical trial data, such as the Heart Protection Study, Collaborative Atorvastatin Diabetes Study, etc., there are clear guidelines with regard to the use of statin therapy in T2DM; however, with respect to T1DM, in North America, there does not appear to be any clear guideline (4, 5, 6, 7, 13, 14). In the present report, we show that in young patients with T1DM (mean age 23.4 yr), simvastatin therapy resulted in a moderate but significant reduction in both LDL and non-HDL cholesterol. In addition, low-dose simvastatin therapy in T1DM was safe and there were no instances of liver transaminases exceeding two times the upper limit of normal, and there was no incidence of myalgia, myopathy, or rhabdomyolysis over the 3-month period.

Inflammation is pivotal to all phases of atherosclerosis from the nascent lesion to plaque rupture (15). In T1DM, CRP was independently correlated with carotid intima-media thickness (16) and impaired coronary vasoreactivity in T1DM (r = –0.70, P = 0.001) (17). In the European Diabetes study, Schram et al. (18) have shown that markers of inflammation (CRP, IL-6, and TNF), combined in a Z-score, were significantly associated with albuminuria, retinopathy, and CAD. Interestingly, Colhoun et al. (19) reported that CRP levels were significantly higher in diabetic women, compared with matched controls, and might reflect insulin resistance in a population in which the relative risk for coronary heart disease is much higher than T1DM men. A novel observation of the present study is that low-dose statin therapy had a concomitant benefit on the lipid profile and inflammatory biomarkers. The antiinflammatory effects reported in this paper include a reduction in plasma levels of CRP, soluble CD40 ligand, and IL-8. Whereas simvastatin therapy has previously been shown in other populations to decrease plasma CRP, cytokine, and chemokine levels (20, 21), there is a paucity of data in T1DM. In addition to testing the effect of simvastatin therapy on systemic biomarkers of inflammation, we also examine the effect of simvastatin therapy on monocyte biology. As reported recently by our group (3), monocytes from T1DM exhibit increased protherogenic activity as evidenced by increased superoxide anion and proinflammatory cytokine release. Also, in a recent report (12), we showed that simvastatin therapy in patients with metabolic syndrome, a harbinger of diabetes, significantly decreased hsCRP levels and resulted in a significant reduction in plasma and lipopolysaccharide-activated monocytic release of IL-6 and TNF and decreased NFKb in monocytes, compared with placebo.

In this report, in T1DM patients, we demonstrate that simvastatin therapy results in significant inhibition of LPS-stimulated release of monocyte superoxide anion, IL-8, and TNF. Also, there was a significant reduction of monocyte IL-6 release in the simvastatin group, compared with baseline. Furthermore, simvastatin therapy resulted in a substantial reduction in NFKb activity (61%) in monocytes despite a moderate lowering of LDL cholesterol (15%). Previously Hofmann et al. (22) have shown increased NFKb activity in peripheral blood mononuclear cells of T1DM with diabetic nephropathy, which was reduced with 600 mg/d {alpha}-lipoic acid. It can be hypothesized that the reduction in NFKb activity in monocytes with simvastatin therapy could result in decreased inflammation and release of cytokines and chemokines such as IL-6 and IL-8, which have {kappa}B elements in their promoter. Whereas only 50% of patients were at the ADA recommended goal of HbA1c, less than 7%, there was no significant differences with respect to the effect of simvastatin on biomarkers of inflammation when patients with HbA1c less than 7 or greater than 7% were compared.

In a previous report in a small cohort, Fried et al. (23) reported a beneficial effect of simvastatin therapy on the lipid profile in T1DM. The novel findings in the present report are that statin therapy in this young predominantly normolipidemic North American T1DM population appears to have beneficial effects on the lipid profile and inflammation, both of which are critical contributors to premature atherosclerosis. Furthermore, in the present study, which had a duration of 3 months, and the study of Fried et al. (23), which included 39 patients, all of whom completed 6 months of study and 36 of whom completed 1 yr of study, no significant side effects were encountered. These findings should prompt a multicenter clinical trial investigating the safety and efficacy of statin therapy on surrogates of cardiovascular disease such as carotid intima-media thickness in T1DM. However, whereas such studies are being undertaken, it is not unreasonable to propose that statin therapy be used for the prevention of premature atherosclerosis in this high-risk population.

In the recently published joint British guidelines in prevention of cardiovascular disease in clinical practice (24), it was suggested that statin therapy be instituted in patients with diabetes mellitus if they are older than 40 yr with T1DM or T2DM, for patients 18–39 yr with T1DM or T2DM who have at least one of the following: retinopathy, nephropathy, poor glycemic control (HbA1c > 9%), elevated blood pressure requiring antihypertensive therapy, raised total cholesterol greater than 240 mg/dl (the authors’ preference would be in those with LDL cholesterol ≥ 130 mg/dl), features of metabolic syndrome and family history of premature in cardiovascular disease in a first-degree relative.

Given the important role of inflammation in the genesis of premature cardiovascular disease, serious consideration should be given to statin therapy as recommended by the British guidelines in T1DM patients, based on the benefits of statin therapy in other populations (24, 25, 26). Furthermore, in both Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction and Reversal of Atherosclerosis with Aggressive Lipid Lowering (25, 26), the concomitant reduction in both LDL cholesterol and hsCRP resulted in the greatest benefit. Whereas it may not be appropriate to institute statin therapy in all young T1DM patients, it is not unreasonable to consider statin therapy in patients with moderate to high risk; however, caution must be exercised in younger women because of the risk for pregnancy. In conclusion, the present study makes the novel observation that simvastatin therapy is safe and has concomitant benefits on both the lipid profile and biomarkers of inflammation in patients with T1DM.


   Footnotes
 
This work was supported by the Juvenile Diabetes Foundation and National Institutes of Health Grants K24 AT00596 and R21DK69801.

Disclosure: I.J., E.M., S.C.G., and S.D. have nothing to declare.

First Published Online May 22, 2007

Abbreviations: CAD, Coronary artery disease; CRP, C-reactive protein; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; hsCRP, high-sensitivity CRP; LDL, low-density lipoprotein; LPS, lipopolysaccharide; NFKb, nuclear factor-{kappa}B; sCD40L, soluble CD40 ligand; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

Received February 27, 2007.

Accepted May 15, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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