Anti-thrombotic therapy in diabetic patients: revisited

Keywords::

• anti-thrombotic therapy
• atherothrombosis
• diabetes mellitus
• diabetic platelets
• hypercoagulability

Relevant findings

Patients with diabetes, particularly those with Type 2 diabetes, exhibit increased platelet reactivity and a reduced inhibition in response to platelet inhibitors. Hyperglycemia contributes to greater platelet reactivity through direct effects and by promoting glycation of platelet proteins. Pathologic, angiographic and other studies have shown that diabetes favors diffuse and accelerated progression of atherosclerosis. Plaques of diabetic patients are more commonly complicated and are at greater risk of subsequent events. Moreover, diabetics who die suddenly show an increased number of fissured atherosclerotic plaques compared with nondiabetics. The results of angioscopic examination show that diabetics with unstable angina have a higher incidence of plaque ulceration and intracoronary thrombus formation than nondiabetics. Plaques of diabetic patients usually also have a greater lipid core burden, a richer inflammatory component, and are more commonly complicated by overlying thrombosis.

In diabetes mellitus, activation of the intrinsic coagulation pathway occurs more easily and fibrinolysis is decreased. Increased platelet reactivity involves intensified adhesion and aggregation in patients with diabetes mellitus or those at high risk for the disease. Subjects at various stages of diabetes proved to have increased numbers of activated platelets compared with healthy controls. Being in line with the so-called ‘response-to-injury’ theory in subjects with clinically overt angiopathy, newly diagnosed insulin-dependent diabetes patients already show clearly increased levels of circulating activated platelets with exposed adhesion molecules. Moreover, this activation is not related to the improvement of glycemic control with intensified insulin therapy. A subpopulation of large, hyperactive platelets, circulates in patients with diabetes mellitus, at a level similar to that predicted from the results with patients who have experienced myocardial infarction. This suggests that the elevated potential for aggregation of such platelets lowers their threshold for activation, thus contributing to the increased incidence of acute cardiovascular events in diabetes mellitus (for review see [1,2]).

Current anti-thrombotic strategies

Diabetic patients have an increased risk of atherothrombotic events, in part attributed to platelet dysfunction and hyperactivation, warranting the use of platelet-inhibiting strategies in order to reduce their ischemic risk. Although currently approved, antiplatelet treatment strategies have proven useful in improving outcomes, diabetics continue to have a higher risk of adverse cardiovascular events compared with that in nondiabetics owing to reduced antiplatelet drug responsiveness, including resistance to currently used oral antiplatelet agents. Novel and more potent antiplatelet agents currently under clinical development will be useful in efforts to reach these therapeutic goals (for review see [3]).

Essentially, there are three different classes of platelet-inhibiting drugs: cyclooxygenase-1 (COX-1) inhibitors acetyl salicylic acid (ASA), ADP-receptor antagonists (thienopyridines) and platelet glycoprotein (GP) IIb/IIIa inhibitors, which are mostly used for the prevention and treatment of atherothrombotic disorders. ASA inhibits the COX-1 enzyme and blocks platelet thromboxane A2 synthesis. However, patients on ASA therapy, particularly those at high risk, may continue to have recurrent thrombotic events. The use of ASA in primary prevention is a matter of debate. GP IIb/IIIa inhibitors are very potent antiplatelet agents, being effective through inhibition of the final common pathway that mediates the platelet aggregation processes. GP IIb/IIIa inhibitors are used to prevent thrombotic complications in high-risk patients undergoing percutaneous coronary interventions. Their limited availability (parenteral use only) and short duration of action impedes their use for long-term protection. As a third strategy, the irreversible blockade of the platelet ADP thienopyridine derivatives was discovered. Ticlopidine as a first-generation agent and its combination with ASA is associated with a more enhanced inhibition of platelet function and better clinical outcomes in patients undergoing coronary stenting compared with ASA monotherapy or ASA plus warfarin. However, the limited safety profile of ticlopidine and its inability to achieve antiplatelet effects rapidly have led clopidogrel, a second-generation thienopyridine, to become the ADP-receptor antagonist of choice. The Reduction of Atherothrombosis for Continued Health (REACH) registry is an international, prospective and contemporaneous cohort of nearly 70,000 patients with at least three atherothrombotic risk factors, or established atherothrombotic disease in at least one site. Approximately 30,000 of the REACH patients have diabetes mellitus. The major adverse cardiac events rate at 1 year was positively related to the number of atherothrombotic anatomic sites in diabetic and nondiabetic subjects, and the rate was significantly higher in those with than without diabetes. Diabetic patients with risk factors only had a significantly lower major adverse cardiac events rate than nondiabetic subjects or diabetic patients with established atherothrombotic disease. Thus, diabetic patients in the REACH registry have an increased risk of cardiovascular events compared with nondiabetic subjects, related to the number of atherothrombotic sites. However, although increasing the risk, diabetes may not be truly equivalent to previous atherothrombotic events for predicting future cardiovascular event rates [4]. The post hoc analysis of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance (CHARISMA) trial clearly showed that patients with risk factors do not profit from a combination of therapy of ASA and clopidogrel, but those with clinically evident atherothrombosis do [5]. Several new substances targeting the ADP receptor became available or will be available shortly, comprising irreversible (prasugrel) or reversible inhibitors (ticagrelor, cangrelor). Results from the diabetic subgroup of the Trial to Assess Improvement in Therapeutic Outcomes by Optimising Platelet Inhibition with Prasugrel – Thrombolysis in Myocardial Infarction-38 (TRITON-TIMI-38 trial) show that regarding the primary end point (comprising of cardiovascular death and nonfatal myocardial infarction or nonfatal stroke) the risk was significantly reduced among patients with diabetes mellitus who were given with prasugrel. The net clinical benefit with prasugrel was greater for subjects with diabetes than for subjects without diabetes. Thus, the more intensive oral antiplatelet therapy given with prasugrel is of particular benefit to patients with diabetes [6].

Adapted guidelines

Existing guidelines recommend the use of low-dose ASA for the primary prevention of cardiovascular events in patients with diabetes, but definitive evidence supporting its efficacy is lacking. Recently, the American Diabetes Association (ADA) published their updated Standards of Medical Care in Diabetes document and one of the major changes was with regard to ASA recommendations in primary prevention patients. Prior to this update, the ADA recommended ASA 62–75 mg per day for primary prevention in patients with Type 1 or Type 2 diabetes who were at increased cardiovascular risk. This included patients over 40 years of age or who had additional risk factors for cardiovascular disease, such as a family history of cardiovascular disease, hypertension, smoking, dyslipidemia or albuminuria [7]. Now the ADA recommends ASA for primary prevention in patients with diabetes who have a 10-year risk of a cardiovascular event of greater than 10%. This probably includes men over 50 years of age and women over 60 years of age who have at least one additional risk factor for cardiovascular disease [8]. This modification takes into account the meta-analysis by De Berardi evaluating large trials, including the Physicians’ Health Study (PHS), the Early Treatment of Diabetic Retinopathy Study (ETDRS), the Primary Prevention Project (PPP), the Women’s Health Study (WHS), the Prevention of Progression of Arterial Disease and Diabetes (POPADAD), and the Japanese Primary Prevention of Atherosclerosis with ASA for Diabetes Study (JPAD) [9]. The analysis included all-cause mortality, death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke in patients receiving ASA compared with those receiving no treatment or placebo. No significant difference in the risk of major cardiovascular events, all-cause mortality, death from cardiovascular causes, risk of heart attack or risk of stroke was found. After separation according to gender, it was found that ASA significantly reduced the risk of myocardial infarction in men, but no significant difference was found among women taking ASA with regard to myocardial infarction in men. The authors concluded that a clear benefit of ASA for primary prevention of cardiovascular events in patients with diabetes has not been proven and that gender may be an important factor [9]. Recently, Stavrakis et al. analyzed data from five randomized, controlled trials comparing low-dose ASA versus placebo or no treatment in diabetics with any previous history of cardiovascular disease. ASA was associated with a nonsignificant reduction in the hazard rate of the composite end point of major cardiovascular events compared with control. Similarly, there was a nonsignificant reduction in the hazard rate of the individual end points of myocardial infarction, stroke, cardiovascular and all-cause mortalities. The risk of major bleeding increased nonsignificantly with ASA compared with control [10].

Thus, the use of ASA in the primary prevention of cardiovascular disease or in patients with diabetes mellitus, or in those with peripheral vascular disease is not supported by the current evidence. ASA therapy has significant benefits in a variety of clinical settings as demonstrated by recently published meta-analyses. Current evidence suggests that ASA is beneficial for secondary prevention for cardiovascular disease, primary prevention of pre-eclampsia and secondary prevention of colorectal adenomas. The benefits of ASA use must be weighed clinically against the risk of adverse events such as gastrointestinal and intracranial bleeding.

Conclusion

The atherosclerotic process in patients with diabetes mellitus begins earlier, progresses faster and is localized more peripherally compared with nondiabetic individuals. Patients with diabetes mellitus experience cardiovascular events earlier than unaffected individuals, and may have more diffuse and severe underlying pathologies, leading to silent and undetected events. The prognosis is worsened in the preceding phase of glucose intolerance, implied the metabolic disease in a network of classical risk factors (hypertension, dyslipoproteinemia or obesity) with a background of genetically programmed susceptibility. The prothrombotic milieu, which involves platelet hyper-reactivity, increased coagulation markers, as well as a decreased fibrinolytic potential, contributes to the worsened clinical outcome despite the combined use of antiplatelet and anti-thrombin agents. Combined anti-thrombotic and individualized therapeutic strategies are mandatory to reduce the increased atherothrombotic risk in diabetic patients.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.