Utility of Aspirin Therapy in Patients With the Cardiometabolic Syndrome and Diabetes

The cardiometabolic syndrome (CMS), which includes a hypercoagulable state among several hemodynamic and metabolic abnormalities, leads to substantial increases in cardiovascular disease (CVD) morbidity and mortality. The diagnosis of the syndrome can be made when an individual has 3 of 5 components: increased waist circumference, increased triglycerides, low high-density lipoprotein cholesterol, increased blood pressure, and increased glucose. According to National Health and Nutrition Examination Survey (NHANES) III data using Adult Treatment Panel (ATP) III guidelines, between 21% and 24% of adults in the United States meet criteria for CMS. Affected individuals have approximately a 3-fold higher prevalence of coronary heart disease, myocardial infarction, and stroke. Hyperglycemia or dysglycemia (glucose levels above normal but not necessarily high enough for a patient to be classified as diabetic) are also associated with a continuum of CVD risk.¹ CMS is also linked to type 2 diabetes mellitus (T2DM), and by one estimate 92% of patients with T2DM have CMS. Although all of the mechanisms leading to increased CVD risk in CMS have not been fully elucidated, increased platelet aggregation/adhesion, endothelial dysfunction, and hypercoagulability are likely important contributors. In this review, we will iterate the pathophysiologic underpinnings of these metabolic and cardiovascular abnormalities and the potential role of aspirin in reducing CVD in patients with CMS and T2DM.

Platelets

Increased platelet aggregation and adhesion have an established role in acute arterial thrombosis, and agents directly targeting the prevention of platelet aggregation/adhesion have therapeutic benefits in the treatment of acute coronary syndrome² and stroke.³ The process of thrombus formation is complex and involves a number of mediators. In response to vascular injury, platelets interact with collagen and von Willebrand factor (vWF) in the subendothelial matrix via their respective receptors, glycoprotein (GP) VI and GPIb/V/IX.⁴ This interaction leads to structural changes in platelets with subsequent release of ADP and thromboxane A2 (TxA2) and formation of thrombin on the surface of the platelets, leading to the recruitment of more platelets and causing further activation and amplifying the injury response. Integrin GPIIb/IIIa of untreated platelets interact with adhesive proteins, particularly fibrinogen and vWF, resulting in platelet aggregation.⁴ Thrombus formation then ultimately results from the interplay of thrombin, fibrin, and the platelet.

In addition to their role in thrombus formation, platelets also play a significant role in atherosclerotic disease through the release a number of inflammatory mediators. In animal models of atherosclerotic vascular disease, activated platelets promote monocyte recruitment to the involved vessels, with resultant disease progression via the delivery of chemokines on the surface of inflammatory and endothelial cells.⁵

Platelet dysfunction in CMS has not been studied directly; however, there is a substantial amount of information about platelet function in patients with T2DM, obesity, and/or insulin resistance, all of which have a very close association with CMS. Platelet-dependent thrombosis is increased with increasing levels of fasting glucose, even within a range of glucose that would generally be considered normal.^1,6 Also, central obesity in nondiabetic women with normal lipid values is associated with increased platelet activation, which is reversible with weight loss.⁷ In this regard, increased in vitro leptin levels, consistent with levels found in obese individuals, have been found to act synergistically with ADP to activate platelets.⁸ Also, persons with T2DM have been found to have increased sensitivity of platelet purinergic receptors to ADP. This leads to an increased number of circulating platelet microaggregates, which can serve as a nidus for thrombus formation. The reversibility of these microaggregates was inversely associated with levels of hemoglobin A_1c.⁹ Hypertriglyceridemia, one of the defining features of CMS, also increases platelet aggregation, likely via very-low-density lipoprotein cholesterol stimulation of CD36 ligand causing increased production of TxA2.¹⁰ Triglycerides also are the source of free fatty acids utilized in the production of TxA2, which is a crucial player in platelet aggregation. Tight metabolic control in T2DM has been shown to result in a significant reduction of in TxA2 biosynthesis. There is also increased platelet surface expression of GPIb and GPIIb/IIIa in persons with T2DM and inappropriate basal platelet activation, as evidenced by increased levels of intracellular Ca⁺⁺ and platelet activation markers such as P-selectin, CD40L, and CD63.¹¹ Furthermore, platelets from obese insulin-resistant individuals have impaired response to the antiaggregating effects of nitric oxide and prostacyclin due to diminished production of these compounds as well as reduced activity of the second messengers cGMP and cAMP.¹² They are also resistant to the normal antiaggregating effects of insulin^10,13 and the normal inhibition, by insulin, of platelet deposition on collagen.¹³ Collectively, these data suggest that both insulin resistance and hyperglycemia contribute to the enhanced platelet aggregation and adhesion seen in patients with obesity and T2DM.

Role of the Endothelium in Platelet Aggregation and Adhesion

Under normal physiologic conditions, a healthy endothelium inhibits platelet adhesion and exerts other antiatherosclerotic actions on the vasculature. It has important roles in regulation of vascular tone, thrombolysis, and inflammation. In addition, there is a balance of proaggregatory influences from activated platelets and antiaggregatory influences of the endothelium primarily from the release of nitric oxide and prostacyclin.¹⁴ In T2DM, obesity, and some other metabolically abnormal states, there is a decrease in the release of both substances in part due to effects mediated by increased free fatty acids.^10,14 In addition, there is evidence that increased levels of leptin, as found in obese individuals, down-regulates thrombomodulin, which is an important endothelial anticoagulant enzyme.⁸ Thus, endothelial dysfunction in association with metabolic disorders is associated with decreased defenses against platelet adhesion.

Hypercoagulability in T2DM and CMS

In addition to platelet dysfunction, multiple other coagulation pathways are abnormal in individuals with CMS. There is impaired fibrinolysis, in part due to elevated plasminogen activator inhibitor 1 (PAI-1) levels.^10,15 Increased PAI-1 levels are associated with thrombotic disorders, including myocardial infarction, and are an important predictor of the development of T2DM.¹⁵ Several components of CMS contribute to this elevation of PAI-1: One is insulin resistance and resulting hyperinsulinemia, possibly independent of hyperglycemia, as there is an insulin promoter site on the PAI-1 gene.¹⁵ Another factor promoting increases in PAI-1 are the elevations in triglycerides and very-low-density lipoprotein cholesterol, which also promote PAI-1 synthesis.¹⁰ Furthermore, PAI-1 is also produced by platelets in excessive amounts by visceral adipocytes.¹⁶ Hypercoagulation may also be promoted by other adipokines produced by visceral fat, such as tumor necrosis factor α (TNF-α), adiponectin, interleukin-6, and others, in association with CMS.¹⁶ There is also increased activation of factor VII as well as increased levels of fibrinogen and vWF in obesity, CMS, and T2DM.

Abnormalities of visceral fat and its metabolic function may provide a common precursor insulin resistance, lipid abnormalities, and abnormalities in coagulation/fibrinolysis. Visceral fat produces proinflammatory cytokines such as interleukin-6 and TNF-α, which in turn elevate fibrinogen levels. These cytokines are responsible for some of the endothelial dysfunction that causes an increase in vWF. Factor VII, a key element in stimulating the tissue factor–induced extrinsic clotting cascade, is abnormally activated in persons with CMS. There is also some experimental evidence to support the notion that the coagulopathy is driven by hyperglycemia rather than hyperinsulinemia.¹⁵ Nevertheless, most studies have found a relation of either hyperinsulinism or hypertriglyceridemia to specific abnormalities in coagulation.¹⁰

Aspirin Therapy in CMS and Diabetes

Early descriptions of a medical role for salicylic acid occurred over 100 years ago when it was discovered to have anti-inflammatory properties. Salicylic acid gave way to acetylsalicylic acid (aspirin) and was used widely for the treatment of rheumatism. Through subsequent years, the uses of and indications for aspirin have evolved, and the basis of therapeutic indications has been predicated on its vasodilatory, anti-inflammatory, and antithrombotic effects. Today, aspirin remains the most commonly used medication for the treatment of pyrexia, pain, and inflammation; however, its role in the prevention and treatment of acute coronary syndrome¹⁴ as well as ischemic stroke prevention is the focus of our review.

Mechanism of Action of Aspirin

The primary action of aspirin lies in the interruption of the synthesis of prostaglandins.^2,14 The production of prostaglandins occurs through the oxidation of arachidonic acid, which is derived from membrane phospholipids. Following oxidation, arachidonic acid is further transformed by prostaglandin H synthase, which is more commonly referred to as cyclooxygenase (COX). COX in turn is responsible for the production of thromboxanes and prostacyclin, which work in opposition to each other, acting as vascular mediators and maintaining vasodynamic function and platelet activity.

COX has 2 separate isoforms, COX-1 and COX-2. COX-1 is a constitutive isoform found in most tissues, whereas the COX-2 isoform is cytokine-induced and found in states of inflammation. Also of therapeutic importance, COX-2, unlike COX-1, is absent in the stomach. Aspirin inhibits both COX isoforms by the irreversible acetylation of serine 530, which impedes the access of arachidonic acid to the active site.¹⁴ The process is similar with COX-2; however, the inhibition on COX-1 is 170-fold greater secondary to differences in substrate channels. As a result of COX-1 inhibition, aspirin has a key antiplatelet effect. This occurs through its inhibition of TxA2, which is a potent platelet agonist and platelet aggregator. Since endothelial cells have synthetic capacity for COX, there is little effect on the production of prostacyclin. Because its binding of COX-1 is irreversible and platelets lack synthetic capacity, aspirin permanently eliminates the aggregatory properties of affected platelets (Figure 1).¹⁴

Another effect of aspirin is to decrease thrombin generation. Of interest, this effect is reduced with increasing levels of cholesterol.¹⁷ Although its effect on fibrinolysis is unclear, it alters fibrinogen acylation in normal individuals, making resulting fibrin gels more porous and less well developed.^17,18

Aspirin and Glucose Metabolism

Insulin resistance is the primary pathophysiologic derangement in the development of the abnormal glucose homeostasis seen in patients with CMS. The mechanism by which aspirin influences glucose metabolism is unclear, but several hypotheses have been promoted. Aspirin was first demonstrated to have an impact on glycemic control as far back as 1877, when Ebstein noted that high-dose aspirin therapy resulted in considerable reduction in glucosuria in diabetic patients.¹⁹ In addition, patients who were receiving high doses of aspirin for the treatment of rheumatologic disorders were also noted to have improved glucosuria as well as improved blood glucose levels.¹⁴

One mechanism of action of aspirin involves the modulation of TNF-α. TNF-α levels have been demonstrated to be elevated in individuals with insulin resistance and obesity.^20,21 Fatty acid activation of a serine kinase cascade results in increased levels of TNF-α,^20,21 which has deleterious effects on a number of steps in the insulin signaling pathway, including disruption of insulin metabolic signaling.²¹ TNF-α has been shown to cause serine phosphorylation of insulin receptor substrate 1 (IRS-1), which prevents downstream metabolic signaling (Figure 2).^21,22 One study showed that aspirin inhibited 4 of the 6 serine kinases that have been shown to cause IRS-1 phosphorylation, suggesting that aspirin may enhance insulin sensitivity by protecting IRS-1 from serine phosphorylation, thus allowing optimal tyrosine phosphorylation and downstream signaling through the PI3-kinase and protein kinase B (Akt) pathway.²³

Additional studies have focused on the actions of aspirin on nuclear factor κB. Aspirin and salicylate have been shown to inhibit the activity of nuclear factor κB and its upstream activator IκB-kinaseβ (IKKß). In this model, subcutaneous administration of either high-dose aspirin or sodium salicylate resulted in marked improvement in hyperglycemia, insulin sensitivity, and dyslipidemia in insulin-resistant obese rodents.²⁴ The authors of this study further demonstrated the importance of IKKß by showing that IKKß knockout models were protected against insulin resistance development and thus demonstrating that the beneficial effect was not secondary to the inhibition of COX.²⁴

The effects of aspirin on glucose homeostasis in patients with insulin resistance seen in CMS are less clear. One study evaluated the use of high-dose aspirin and its role in glucose metabolism in patients with T2DM.²⁵ In this study, 9 patients with T2DM were treated with approximately 7 g of aspirin daily and followed for 2 weeks. Significant improvement in fasting plasma glucose (∼25%), reduction in total cholesterol (∼15%), reduction in C-reactive protein (∼15%), and reduction in triglycerides (∼50%) were found at the end of this trial.²⁵ While this study showed significant benefit, albeit in a small trial with supratherapeutic dosing, other trials have produced inconsistent results.

Aspirin and CVD Risk

Aspirin as a CVD preventative agent was first examined in secondary prevention trials. The major studies in this area have been aggregated in the meta-analysis by the Antithrombotic Trialists’ Collaborative,²⁶ which showed a significant preventive effect of antiplatelet therapy on serious cardiovascular event outcomes, myocardial infarction, and stroke in patients that had preexisting evidence of vascular disease either due to history of a prior event or intervention. Also included in this meta-analysis were a small number of studies that analyzed patients without prior acute events or interventions who were at increased risk for CVD due to the presence of comorbid diseases such as T2DM, carotid artery disease, or end-stage renal disease requiring dialysis. When examined as a separate subpopulation, this group of high-risk individuals had nearly identical statistically significant degrees of protection as the subpopulation with a history of vascular events.

In the last 20 years, there have been 6 major trials to assess the efficacy of aspirin in the primary prevention of CVD.^27–32 They have had mixed results with respect to achieving their primary end points of reduction of CVD events (myocardial infarction or composite end point of stroke, myocardial infarction, and CVD death). The Hypertension Outcome Trial (HOT)²⁹ showed a relative risk (RR) (aspirin vs placebo) of the composite cardiovascular disease end point of 0.85 (95% confidence interval [CI], 0.73–0.99),²⁹ the Thrombosis Prevention Trial³¹ showed an RR (aspirin vs placebo) of ischemic heart disease of 0.80 (95% CI, 0.65–0.99),³¹ and the aspirin component of the Physicians Health Survey²⁷ showed an RR (aspirin vs placebo) of myocardial infarction of 0.56 (95% CI, 0.45–0.70).²⁷ On the other hand, the Primary Prevention Study²⁸ failed to reproduce these results as they were unable to show a statistically significant difference in the predefined primary end point or secondary end point of myocardial infarction. However, a secondary end point consisting of the primary end point with the addition of transient ischemic attack, peripheral artery disease, revascularization, and angina pectoris showed significant reduction.²⁸ Also negative were the British Male Doctors Study,³⁰ which had no outcome that reached significance other than reduction in transient ischemic attack, and the Women’s Health Study,³² which failed to reach significance in its primary end point but showed a significant reduction in stroke, a predefined secondary end point, with aspirin vs placebo. These studies included populations selected for increased cardiovascular risk^28,29,31 and populations not selected for increased cardiovascular risk.^27,30,32

A meta-analysis including the British Male Doctors Study and Primary Prevention Study showed an overall reduction in CVD events driven entirely by a reduction in the RR of nonfatal myocardial infarction by 32% (RR, 0.68; 95% CI, 0.59–0.79) for the aspirin group as compared to placebo. Data on stroke and vascular death remained inconclusive. Among the 11,466 females included in this meta-analysis, no statistically significant difference was shown between aspirin and placebo.³³

The Women’s Health Study³² showed very different results from the other aspirin trials. The risk of vascular event was not significantly reduced, at 9% (RR, 0.91; 95% CI, 0.80–1.03), and the risk of myocardial infarction, which had driven the results of the previous studies and thus the meta-analysis, was not influenced (RR, 1.02; 95% CI, 0.84–1.25). However, the risk of stroke was significantly decreased by 17% (RR, 0.83; 95% CI, 0.69–0.99).³²

Many theories exist about why such different results were observed in the 2 largest trials of reportedly healthy individuals receiving aspirin for primary prevention, apparently based on sex.^27,32 One possibility would be a true sex difference in platelet reactivity. Indeed, a recent study found that women’s platelets are more reactive to 10 of 12 common in vitro aggregation agonists and that after treatment with aspirin some of this reactivity remains unaffected. However, they achieved complete suppression of the COX-1 pathway, which as stated above is the hypothesized method of cardioprotection.³⁴ Also, the average age of the men and women in these studies was comparable, an important fact because atherosclerosis typically develops about 10 years later in women than in men. Indeed, when the Women’s Health Study data were analyzed for women older than 65 years, there was a significant reduction of 26% (95% CI, 8%–41%) in the major cardiovascular event category and 34% in myocardial infarction.³² One final possibility is the difference in dosage. The Physicians Health Study used 325 mg every other day vs the Women’s Health Study dosage of 100 mg every other day.^27,32 Analysis of these and other studies by Dalen³⁵ suggests that the minimum dose of aspirin for the primary prevention of myocardial infarction in men older than 50 is approximately 160 mg and that in women the dosage is undetermined but likely >100 mg/d.

The evidence supporting a cardioprotective effect of aspirin in T2DM is controversial. Although no large trial has specifically examined the use of aspirin as secondary prevention only in patients with diabetes and prior vascular events, diabetic patients in the studies reported in the Antithrombotic Trialists’ Collaborative²⁶ meta-analysis had risk reductions similar to those in nondiabetics.²⁶ The Antithrombotic Trialists’ Collaborative²⁶ meta-analysis looked at a subset of 9 trials comparing antiplatelet therapy to control therapy in 4961 diabetics and showed a nonsignificant reduction of 7% in serious vascular events.²⁶ The Early Treatment in Diabetic Retinopathy Study (ETDRS),³⁶ which contributed the bulk of the patients to this analysis, had particularly interesting findings. Because approximately 30% of the participants in both the aspirin and placebo groups had evidence of macrovascular disease at study entry, it can be viewed as a mixed primary and secondary outcome trial in diabetics. When the primary outcome of all-cause mortality between the aspirin and placebo groups was evaluated at 5 and 7 years, no difference was observed. Analysis at 5 years revealed a significant reduction in the predetermined secondary end point of fatal and nonfatal myocardial infarction (RR, 0.72; 99% CI, 0.55–0.95). However, at 7 years this effect was no longer statistically significant. A caveat of this study is that all patients had to have proliferative retinopathy and thus may have had diabetes for a longer period of time and may have had a history of worse glycemic and blood pressure control.

Collectively, available data demonstrate a variable response to aspirin in patients with CMS. Platelets from affected individuals exhibit increased activation via thromboxane-dependent and thromboxane-independent pathways as well as resistance to normal antiaggregating influences. One example of this is the increased microaggregates due to P2Y12 activation that were reversed with ticlopidine but not aspirin.⁹ Also, aspirin does not affect PAI-1 levels,³⁷ one of the major components of poor fibrinolysis in CMS, though it may reduce plasmin-induced PAI-1 activity,³⁸ nor does it directly affect elements of the extrinsic pathway.³⁷

Aspirin resistance is a problematic term that is sometimes used to describe the variable results seen with aspirin therapy. It is defined either clinically as continued ischemic events in patients receiving aspirin or as in vitro failure of the antiaggregatory effect of aspirin on platelets as measured by various techniques. Prevalence estimates range from about 6% to 60% depending on the technique used, with wide variation between techniques even within the same sample. “Sensitivity” to aspirin also appears to vary within an individual depending on their current physiologic status and changing with parameters such as blood pressure and state of health.³⁹

In summary, there are limited data on the utility of aspirin treatment in patients with CMS. Although aspirin has been shown to be beneficial in high-risk individuals, most of these persons had ischemic heart disease or T2DM. The benefits in individuals with CMS were not assessed, but without established T2DM or ischemic heart disease. While the benefit in patients with T2DM and no ischemic heart disease seems well documented, most of the data come from the ETDRS and most of the patients included had long-standing T2DM and likely poor glycemic and blood pressure control, as evidenced by their degree of retinopathy; they were also less likely to be receiving aggressive lipid therapy.

Many of the factors resulting in the hypercoagulable state of CMS are not significantly affected by acetylsalicylic acid therapy, and thus benefit cannot be assumed. At present, the low cost and good side effect profile for low-dose aspirin and its benefit in diabetic and other high-risk patients likely justifies its use in patients with CMS. On the other hand, prospective controlled trials are needed in patients who have CMS but no vascular disease or T2DM, and their results will certainly help to better characterize the impact of aspirin in patients with CMS.