Elsevier

Journal of Diabetes and its Complications

Volume 30, Issue 7, September–October 2016, Pages 1365-1370
Journal of Diabetes and its Complications

Statin therapy and inflammation in patients with diabetes treated with high dose aspirin

https://doi.org/10.1016/j.jdiacomp.2016.05.002Get rights and content

Abstract

Background

Statin and aspirin form the therapeutic cornerstone in patients with coronary artery disease (CAD) and diabetes. Little is known about relationship of statins with blood thrombogenicity and inflammation in these patients.

Methods

Two hundred nine consecutive patients with diabetes and suspected CAD undergoing elective cardiac catheterization were divided in groups based on statin treatment in the Multi-Analyte, Thrombogenic, and Genetic Markers Atherosclerosis study. Urinary 11-dehydrothromboxane B2 (11-dh-TxB2), lipid profile and oxLDL/β2GPI were measured by AspirinWorks™ ELISA assay, vertical density gradient ultracentrifugation and immunoassay respectively. Thrombelastography, and ADP- and collagen-induced light transmittance aggregometry assessed thrombogenicity. CAD was classified as none/minor [< 20% diameter stenosis (DS)], moderate (20–75% DS), or severe (> 75% DS).

Results

Severe, moderate, and no CAD was observed in 66, 19, and 15% of patients respectively. Patients on statins had significantly lower 11-dh-TxB2, collagen-induced aggregation, total cholesterol, total LDL, LDL3, oxidized-LDL, Apo B100, and ApoB100/A1 ratio (p < 0.01 for all). Statin therapy demonstrated a lower proportion of patients with high urinary 11-dh-TxB2 (> 1500 pg 11-dh-TxB2/mg creatinine) (25 vs. 57%, p = 0.01).

Conclusion

Statins along with aspirin, confers additional anti-inflammatory and antithrombotic effect in diabetics with CAD. Urinary 11-dh-TxB2 may be a useful biomarker for personalizing statin therapy.

Introduction

There is a rapidly increasing incidence of diabetes with estimated projected prevalence of > 500 million by 2035 (Guariguata et al., 2014). Studies have shown that diabetes accelerates formation and propagation of atherosclerotic plaque that leads to worsening severity of coronary artery disease (CAD) (Colwell et al., 1981, Creager et al., 2003). In fact, approximately two-thirds of patients suffer from diabetes die because of cardiovascular complications (Cardiovascular Disease & Diabetes, 2012). Recent literature has linked diabetes with cardiovascular disease to have a common underlying pathophysiology of chronic inflammation (Lee et al., 2009, Strissel et al., 2014).

Pre-clinical studies have demonstrated immune infiltration of pancreatic islets in mice suffering from early diabetes. The underlying mechanism was thought to be subclinical inflammation which along with interaction of metabolic factors, like obesity, leads to immune infiltration of various tissues including liver, skeletal muscle and pancreatic islet cells among other tissues (Plesner, Ten Holder, & Verchere, 2014). The secretion of inflammatory markers in these tissues has been shown to increase insulin resistance, which leads to a vicious cycle of insulin resistance leading to further increase in inflammation and vice-versa (Wang, Zhou, & Graves, 2014). The inflammatory origin of type 2 diabetes also finds support from clinical studies demonstrating elevated levels of inflammatory biomarkers in diabetics (Castoldi et al., 2007, Kristiansen and Mandrup-Poulsen, 2005, Pradhan et al., 2001). Preclinical studies and clinical trials have demonstrated significant benefits in improving insulin sensitivity and beta-cell function with approaches targeting inflammatory mediators like IKK-b-NF-kB (salicylates, salsalate), TNF-α (etanercept, infliximab, adalimumab), IL-1β (anakinra, canakinumab) and IL-6 (tocilizumab) (Esser, Paquot, & Scheen, 2015).

HMG Co-A reductase inhibitors (statins) have also been known to possess anti-inflammatory properties that explains their cardio-protective effect independent of lipid lowering properties (Heeschen et al., 2002). Their anti-inflammatory properties have been highlighted in numerous studies like JUPITER trial and AFCAPS/TexCAPS trial where a significant reduction of cardiovascular events with high CRP levels was seen, independent of LDL lowering (Chello et al., 2003, Downs et al., 1998, Ridker, 2009). Gurbel et al. have shown that concomitant high dose aspirin and statin therapy results in a dose-dependent reduction in inflammation in patients with coronary artery disease (measured using urinary 11-dehydrothromboxane B2) (Singla et al., 2012).

The new ACC/AHA guidelines on lipid management in 2013 discontinued using absolute LDL levels as a goal and focused on percentage reduction of LDL with different intensities statin therapy. These guidelines have translated into widespread usage of high dose statins in diabetic patients with coronary artery disease. The studies showing beneficial effects of statin in preventing progression to diabetes were followed by evidence highlighting a biphasic response of statin therapy in patients suffering from diabetes. In a study by Józkowicz and colleagues, simvastatin at low doses induced VEGF synthesis, increased endothelial progenitor cell activity and helped early healing of diabetic ulcers. However, at higher doses and prolonged treatment, it did not result in increased VEGF (Dulak & Józkowicz, 2005). These findings corroborated with other preclinical studies on mice demonstrating a biphasic dose-dependent effect of statins on angiogenesis associated with endothelial apoptosis and VEGF signaling. HMG-CoA reductase inhibitors, at low concentrations, enhanced endothelial cell proliferation, migration and differentiation which were, by contrast, inhibited by high doses of statins (Schiefelbein, Goren, Fisslthaler, et al., 2008). This effect has also been reported in clinical studies with a small clinical pilot study (n = 13) which showed that low dose atorvastatin (10 mg) led to healing of all diabetic foot ulcers, whereas 80 mg/day atorvastatin resulted in healing of only 66% of patients with ulcers (Johansen et al., 2009). Moreover, recently Cederburg and colleagues have observed association of developing diabetes with statin therapy in a dose-dependent manner with a 46% increase at high intensity statin therapy (Cederberg et al., 2015). These findings indicate the necessity of personalization of statin therapy based on specific risks of individuals. In this study we aim to investigate the effects of statin therapy on urinary 11-dh TxB2 in patients with CAD and diabetes mellitus.

Section snippets

Methods

This is an observational case series designed to detect differences in urinary 11-dehydrothromboxane levels in patients with diabetes and coronary artery disease on aspirin 325 mg therapy with addition of statin therapy. After institutional review board approval and written informed consent, 209 consecutive patients with suspected severe CAD and diabetes mellitus type 2 on daily 325 mg aspirin therapy were enrolled prior to elective cardiac catheterization in a sub-analysis of the Multi-Analyte,

Demographics

Baseline demographics, laboratory data and cardiac risk profiles were similar between groups (Table 1) except for increased frequency of history of hypercholesterolemia, prior percutaneous coronary intervention, beta blocker usage, and angiotensin converting enzyme usage in patients on statin therapy (p < 0.05 for all). The glycemic control, as measured by hemoglobin A1c levels, was similar between the two groups (7.6 ± 1.5 for patients not on statins vs. 7.2 ± 1.4 for statins, p = 0.30).

CAD and statin therapy

Out of 209

Discussion

Our study demonstrated that statin therapy in patients with diabetes and CAD was associated with (1) reduced inflammation (as measured by urinary thromboxane level) (2) improved lipid profile and (3) reduced thrombogenicity as compared to the population not on statins.

The association of diabetes type 2 and coronary artery disease (CAD) is well established and is the most common cause of mortality in these patients. Studies have shown that both CAD and diabetes fall in the spectrum of chronic

Conclusions

In diabetics with suspected CAD on aspirin, adding lipid lowering therapy was associated with significantly lower levels of inflammation and thrombogenicity. Our data suggest further exploration of urinary 11-dTxB2 for determining intensity of lipid lowering therapy in diabetic patients with CAD.

Acknowledgments

This study was supported by a research grant from Sinai Hospital of Baltimore. Thromboelastography supplies were provided by Haemonetics® Corp. VAP© testing was provided by Atherotech® Inc. Urinary 11-dehydrothromboxane B2 and AtherOx testing was provided by Corgenix Medical Corp. We wish to acknowledge Tania Gesheff RN, MSN, Kiran Kalra, MBBS, and Cescelle Barbour RN, MSN for their contributions to this study.

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  • Disclosures: Paul Gurbel reports serving as a consultant for Daiichi Sankyo/Lilly, Bayer, AstraZeneca, Accumetrics, Merck, Medtronic, Janssen, CSL, and Haemonetics; receiving grants from the National Institutes of Health, Daiichi Sankyo, Lilly, CSL, AstraZeneca, Haemonetics, Harvard Clinical Research Institute, and Duke Clinical Research Institute; receiving payment for lectures, including service on speakers' bureaus, from Lilly, Daiichi Sankyo, and Merck; receiving payment for development of educational presentations from Merck, the Discovery Channel, and Pri-Med; Dr. Gurbel is holding stock or stock options in Merck, Medtronic, and Pfizer; and holding patents in the area of personalized antiplatelet therapy and interventional cardiology. No other authors report any potential conflicts of interest.

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