**Dyslipidemia and Type 2 Diabetes Mellitus: Implications and Role of Antiplatelet Agents in Primary Prevention of Cardiovascular Disease**

Hasniza Zaman Huri

*Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia* 

### **1. Introduction**

78 Dyslipidemia - From Prevention to Treatment

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Cascio W, Devlin RB, Peden DB. Coarse particulate matter (PM2.5-10) affects heart rate variability, blood lipids, and circulating eosinophils in adults with asthma. Dyslipidemia is the major risk factors for macrovascular complications leading to cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM). In addition to this, endothelial dysfunction, platelet hyperactivity, impaired fibrinolytic balance and abnormal blood flow may accelerate atherosclerosis and increased risk of thrombotic vascular events (Colwell & Nesto, 2003). Macrovascular disease is the most common cause of morbidity and mortality in T2DM (Koskinen, 1998). Macrovascular disease is defined as illnesses affecting the larger arteries supplying the heart, brain, and the legs, thereby causing ischemic heart disease, cerebrovascular disease, and peripheral vascular disease (Thompson, 1999). In patients with diabetes, alteration in distribution of lipid increased risk of atherosclerosis. Specifically, insulin resistance and insulin deficiency was identified as phenotype of dyslipidemia in diabetes mellitus (Taskinen, 2003; Krauss & Siri, 2004; Chahil & Ginsberg, 2006). This was characterized with high plasma triglyceride level, low HDL cholesterol level and increased level of small dense LDL-cholesterol (Mooradian, 2008). In these patient also, the increment of free fatty-acid release is due to insulin resistance. With the presence of adequate glycogen stores in the liver, this will promote triglyceride production, which stimulates the secretion of apolipoprotein B (Apo B) and VLDL cholesterol (Mooradian, 2008). Hepatic production of VLDL cholesterol is enhanced due to disability of insulin to inhibit the release of free fatty-acid. Low HDL cholesterol levels were also associated with hyperinsulinemia. There are several associations between dyslipidemia and the increased risk of cardiovascular disease in patients with type 2 diabetes mellitus. Low HDL cholesterol and increased triglyceride levels may contribute to the increased risk of cardiovascular disease. In conjunction with increased small dense LDL cholesterol and low HDL cholesterol levels, further evidence suggests that acceleration of atherosclerosis in diabetes mellitus and insulin-resistant conditions is regulated by hypertriglyceridemia. Nevertheless, the association between LDL cholesterol and CHD risk is stronger compared to the association between hypertriglyceridemia and CHD risk. Type 2 diabetes is also associated with insulin resistance and hyperinsulinemia or syndrome X comprises hypertension, dyslipidemia,

Dyslipidemia and Type 2 Diabetes Mellitus:

triphosphatase (Na+/K+-ATPase) activity (Ferroni et al., 2004).

**mellitus** 

**3. Implications of dyslipidemia and platelet abnormality in type 2 diabetes** 

In patients with type 2 diabetes mellitus, low HDL cholesterol and high triglyceride levels might contribute to the increased risk of cardiovascular disease (Mooradian, 2008). Based on the Expert panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (2011), hypertriglyceridemia, increased small dense LDL cholesterol and low HDL cholesterol found to be important in accelerating atherosclerosis in diabetes mellitus and insulin-resistant conditions. Abnormal platelet function is another important risk factors for cardiovascular disease in patients with diabetes (Colwell & Nesto, 2003). Atherosclerosis and thrombosis contribute significantly to the increased cardiovascular risk of diabetic patients (Colwell, 1997). The majority of ischemic coronary and cerebrovascular events are precipitated by vessel occlusion caused by atherosclerotic plaque disruption, platelet aggregation, platelet adhesion and thrombosis (Colwell & Nesto, 2003). Several systems that involved vasculature such as platelet, endothelial function, coagulation and fibrinolysis are impaired in patients with diabetes (Jokl & Colwell, 1997). Furthermore, increased platelet aggregability and adhesiveness are due to reduce membrane fluidity, increased intracellular Ca2+ and decreased intracellular Mg2+, increased arachidonic acid metabolism, increased

Implications and Role of Antiplatelet Agents in Primary Prevention of Cardiovascular Disease 81

improvement led to a significant decline in their expression (Eibl et al., 2004). In type 2 diabetes patients, platelets increased surface expressionof GP Ib and GP IIb/IIIa (Vinik et al., 2001). GP Ib mediates binding to von Willebrand factor (vWf) which is important in plateletdependent thrombogenesis (Natarajan et al., 2008). Increased expression of GP IIb/IIIa on platelet surfaces leads to enhanced fibrinogen binding, platelet cross-linking and thrombogenesis (Colwell & Nesto, 2003). In patients with type 2 diabetes, decreased platelet insulin receptor number and affinity responsible for platelet hyperactivity (Vinik et al., 2001). Platelets have been shown to be targets of insulin action as they act as functional insulin receptor for insulin binding and autophosphorylation (Vinik et al., 2001). Insulin reduces platelet responses to the agonists' adenosine diphosphate (ADP), collagen, thrombin, arachidonate and platelet-activating factor. (Natarajan et al., 2008). In patients with type 2 diabetes also, platelets show disordered calcium homeostasis (Li et al., 2001). This may cause hyperactivity including platelet shape change, secretion, aggregation and thromboxane formation (Beckman et al., 2002). Furthermore, the deficiency of magnesium in diabetes has been associated with platelet hyperaggregability and adhesiveness (Gawaz et al., 1994). In type 2 diabetes patients, the reduced vascular synthesis of the anti-aggregants prostacyclin and nitric oxide by endothelium, shift the balance towards aggregation and vasoconstriction (Vinik et al., 2001; Ferroni et al., 2004). In type 2 diabetes patients with acute hyperglycaemia, shear stress-induced platelet activation and P-selection expression (Natarajan et al., 2008). Hyperglycaemia also causes non-enzymatic glycation of platelet membrane proteins resulting in changes in protein structure and conformation, as well as alterations of membrane lipid dynamics (Brownlee et al., 1988; Winocour et al., 1992). This could result in enhanced expression of certain crucial platelet receptors, for instance, P-selectin and GP IIb/IIIa, thus altering platelet activity (Ferroni et al., 2004). Glycated LDL causes an increase in intracellular calcium concentration and platelet nitric oxide (NO) production, as well as inhibition of the platelet membrane Na+/K+-adenosine

decreased fibrinolysis and increased procoagulation factors (Serrano Rios, 1998). Besides dyslipidemia, platelet abnormalities contributed significantly to increased risk of CVD in these patients. In patients with type 2 diabetes, the platelet abnormalities are due to increased platelet aggregability and adhesiveness (Colwell & Nesto, 2003) and enhanced platelet aggregation activity may precede development of CVD (Halushka et al. 1981, Mandal et al. 1993). It has been well known that management of dyslipidemia in diabetes mellitus includes lifestyle changes such as increased physical activity and dietary modifications. Besides, various antihyperlipidemic agents have been utilized for this purpose. In contrast, antiplatelet agents are recommended mainly for primary and secondary prevention for cardiovascular disease in T2DM. Dyslipidemia is categorized as one of the cardiovascular risk factors besides others (family history CHD, hypertension, smoking, albuminuria) (American Diabetes Association, 2011). Patients with T2DM and having dyslipidemia are eligible for primary prevention of CVD with antiplatelet agents. This chapter will discuss on different types of antiplatelet agents used as primary prevention of cardiovascular disease in patients with T2DM. It will also emphasize appropriate selection of antiplatelet agents pertaining to clinical conditions of patients with T2DM and dyslipidemia.
