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

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

Dyslipidemia and Type 2 Diabetes Mellitus:

Implications and Role of Antiplatelet Agents in Primary Prevention of Cardiovascular Disease 83

efficacy of aspirin in primary prevention of CVD which included Primary Prevention Project (PPP), US physicians' Health Study (USPHS), Early Treatment of Diabetes Retinopathy Study (ETDRS), Hypertension Optimal Treatment Trial (HOT), British Male Doctors' Trial (BMD) and the Thrombosis Prevention Trial (TPT) (Colwell & Nesto, 2003; Hayden et al., 2002). In Primary Prevention Project (PPP), a low dose aspirin (100 mg/day) was evaluated for the prevention of cardiovascular events in individuals with one or more of the following conditions such as hypertension, hypercholesterolemia, diabetes, obese, family history of premature myocardial infarction or being elderly. After a mean of 3.6 years follow-up, aspirin was found to significantly lower the frequency of cardiovascular death (from 1.4 % to 0.8 %); relative risk (RR) 0.56 [confidence interval (CI) 0.31-.99] and total cardiovascular events (from 8.2 to 6.3% ; RR 0.77 [ 0.62-0.95] ). This trial involved large sample size (n = 4495) with the largest proportion of patients with diabetes mellitus (17%) (Collaborative Group of the Primary Prevention Project, 2001). Overall, PPP provides evidence to prove the efficacy of aspirin in diabetes; though participants were not blinded and were not given placebo pills. Additionally, a meta-analysis done by Hayden et al., (2002) also rated the quality of PPP as "fair" if compared to the rest of studies. In addition to PPP, a 5 years primary prevention trial in 22 701 healthy men; included 533 men with diabetes was conducted in US Physicians' Health Study (USPHS) in which a low-dose aspirin regimen (325 mg every other day) was given to treated group compared with placebo. A total of 44% significant risk reduction in CVD treated group was noted and the subgroup analyses in the diabetes reveals a reduction in myocardial infarction from 10.1 % (placebo) to 4.0 % (aspirin), yield a relative risk reduction of 0.39 for the diabetes men on aspirin therapy (Steering Committee of the Physicians' Health Study Research Group, 1989). Researcher and participants were blinded in this trial. In contrast with PPP, women were included in the study populations (2583 out of 4495 sample sizes). Hence, this study was more reliable compared to previous ones even though only 2% of the study population was diagnosed with diabetes. The Hypertension Optimal Treatment Trial (HOT) also examined the effects of low dose of aspirin (75 mg/day) versus placebo in 18 790 hypertension patients and 8% of them had diabetes. Results showed that aspirin significantly reduce cardiovascular event by 15% and myocardial infarction by 36% (Hansson et al., 1998). The HOT trial was another primary prevention study that included women, which was 46.6 % from total study population. Colwell (2004) commended that this study provided further evidence for the efficacy and safety of aspirin therapy in diabetes with systolic blood pressure less than 160 mmHg. Hayden et al., (2002) was in agreement with Colwell (2004) and concluded that HOT was a "good" quality of trial in their meta-analysis. Despite that, these findings were mirrored by Early Treatment of Diabetes Retinopathy Study (ETDRS) where they reported that although aspirin did not prevent progression of retinopathy but it did produce a significant reduction in risk for myocardial infarction (28%) over 5 years (P=0.038). This study may viewed as mixed primary and secondary prevention trials since those enrolled had a history of myocardial infarction and less than 50% had elevated blood pressure and history of CVD (ETDRS Investigators 1992). Conversely, the British Male Doctors' Trial (BMD) had conflicting results regarding aspirin effects in reducing the risk for myocardial infarction and adverse effects such as gastrointestinal bleeding and hemorrhagic stroke to diabetes patients. A total of 39 % of participants were discontinued therapy during the study due to adverse effect of aspirin (Hayden et al., 2002). Similar to PPP trial, participants in this study were not blinded thus results may be varies. Following this, a meta-analysis of these

TXA2 synthesis, decreased prostacyclin production, decreased NO production, decreased antioxidant levels and increased expression of activation-dependent adhesion molecules (Halushka et al., 1981; Mayfield et al., 1985; Watala et al., 1998; Martina et al., 1998; Trovati et al., 1997; Sarji et al., 1979; Tschoepe, et al., 1997; Leet et al., 1981). For patients with T2DM, the presence of dyslipidemia and platelet hyperactivity justifies the use of antiplatelet agents as primary prevention strategy of CVD.
