**5.3 Ticlopidine**

84 Dyslipidemia - From Prevention to Treatment

five randomized clinical trials (except ETDRS) was performed by Hayden et al., (2002) and systematic reviews on nine articles about the effect of aspirin on gastrointestinal bleeding and hemorrhagic stroke were conducted. They concluded that the net benefit of aspirin increase with CV risk. Nonetheless, this meta-analysis was found to have selection bias due to exclusion of 2 large trials that examined the effects of aspirin in patients with diabetes or stable angina. Sanmuganathan et al., (2001) also reached similar estimates of the beneficial effects of aspirin in primary prevention of CVD. The Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial was the first prospectively designed trial to evaluate the use of aspirin (81 mg or 100 mg) in the primary prevention of cardiovascular events in patients with type 2 diabetes (*n* = 2539) aged 30–85 years in Japan (Ogawa et al., 2008). Among patients aged > 65 years (*n* =1363), aspirin was associated with a 32% reduction in the risk of the primary end point (6.3 vs. 9.2%; *P* = 0.047). Furthermore, in aspirin-treated patients, the incidence of fatal coronary and cerebrovascular events was significantly lower by 90% (0.08 vs. 0.8%; *P* = 0.0037). Paradoxically, there were no differences in nonfatal coronary and cerebrovascular events. Aspirin was well tolerated, with no significant increase in the composite of hemorrhagic stroke and severe gastrointestinal bleeding (Angiolillo, 2009). The outcome of this study was in opposite with the current recommendations on aspirin usage in primary prevention of CVD in diabetes patients (Angiolillo, 2009). However, the ASCEND and ACCEPT-D study are two ongoing trials will provide further insights to the appropriateness of aspirin usage in primary prevention of CVD in patients with diabetes. Another recent trial (POPADAD), failed to show any benefit with aspirin or antioxidants in primary prevention of cardiovascular events (Belch, 2008). The outcome of the study could be due to small number of patients with low event rates. A study on the utilization of antiplatelet therapy in type 2 diabetes patients revealed that many of the eligible patients did not receive the drugs as primary prevention strategy for CVD (Huri et al., 2008). Therefore, the recommendations on aspirin usage in primary prevention of CVD in type 2 diabetes patients must be fully justified after taking consideration against the benefit versus risk of its use. In another words, the recommendations should be base on individual patients' assessment and clinical judgment. Proper use of aspirin in primary prevention of CVD in type 2 diabetes patients may result in

Clopidogrel is another type of antiplatelet agents used in primary prevention of CVD in type 2 diabetes when patients are intolerant to aspirin. It inhibits ADP-induced platelet aggregation by blocking the purinergic receptors and therefore prevents the activation of the GpIIb-IIIa receptor and subsequent binding to fibrinogen (Colwell & Nesto, 2003). Clopidogrel is preferable compared to ticlopidine because of its safety profile (Savi & Herbert, 2005; Bertrand et al., 2000). Nevertheless, the information regarding the usage of clopidogrel in primary prevention of CVD is limited than for secondary prevention of CVD in diabetes patients. Even though clopidogrel may be slightly more effective than aspirin, the size of any additional benefits is statistically uncertain and it has not been granted a claim of superiority against aspirin (Patrono et al., 2004). However, the publication of the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) recently had led to FDA approval of a new indication for clopidogrel in patients with acute coronary syndromes without ST-segment elevation (Patrono et al., 2004).The CURE trial examined CV

long-term benefits.

**5.2 Clopidogrel** 

Ticlopidine also inhibit ADP-induced platelet aggregation with no direct effects on the metabolism of arachidonic acid (Patrono, 1998). It has slower antiplatelet effect compared with clopidogrel (Patrono et al., 2004). Ticlopidine in Microangiopathy of Diabetes (TIMAD) study was conducted by involving 435 patients with nonproliferative diabetes retinopathy to evaluate for its effects on macrovascular disease in diabetes patients. Patients were randomized to receive ticlopidine, 250 mg twice daily and were followed up to 3 years. Ticlopidine was found significantly reduced annual microaneurysm progression by 67% and overall progression of retinopathy was significantly less severe with ticlopidine (TIMAD Study Group, 1990). However, this study was not designed to evaluate effect of ticlopidine on cardiovascular events. There are limited studies done on effect of ticlopidine in prevention of CVD in diabetes. In contrast to clopidogrel, ticlopidine does not have an approved indication for patients with a recent myocardial infarction (Patrono et al., 2004). Even though ticlopidine has lower cost compared to clopidogrel, (Drug Formulary University Malaya Medical Centre, 2005; Patrono et al., 2004), its role in primary prevention of CVD in type 2 diabetes patients have not been established.

#### **5.4 Dipyridamole**

Dipyridamole inhibits platelet cyclic-3',5'-adenosine monophosphate and cyclic-3', 5' guanosine monophosphate phosphodiesterase (Natarajan et al. 2008). Overview of 25 trials among approximately 10000 high risks of CVD patients with the use of dipyridamole and aspirin, it was found that the addition of dipyridamole to aspirin has not been shown clearly to produce additional reductions in serious vascular events (Patrono et al., 2004). However, one of 25 trials suggested that there may be a worthwhile further reduction in stroke (Patrono *et al.* 2004). Patrono et al.*,* (2004) also suggested that the combination of low dose aspirin and extended release dipyridamole (200 mg twice daily) is considered an acceptable option for initial therapy of patients with non-cardioembolic cerebral ischemic events and not in patients with ischemic heart attack. The benefits of dipyridamole in patients with diabetes have not been reported (Natarajan et al., 2008). Specifically, there are limited studies or trials conducted to examine the role of dipyridamole for primary and secondary prevention of CVD amongst T2DM patients.

Dyslipidemia and Type 2 Diabetes Mellitus:

abnormalities increased risk of acquiring CVD.

type 2 diabetes with dyslipidemia.

CVD, thus eligible for primary prevention strategy of CVD.

2007), pp. 2356-2365, ISSN 1432-0428

pp. 531-540, ISSN 1935-5548

1468-5833

**8. Conclusion** 

established.

**9. Summary** 

type 2 diabetes.

**10. References** 

Implications and Role of Antiplatelet Agents in Primary Prevention of Cardiovascular Disease 87

Dyslipidemia is one of the risk factors for acquiring cardiovascular disease in patients with type 2 diabetes. In absent for contraindication, type 2 diabetes patients with dyslipidemia are eligible for primary prevention of cardiovascular disease although the routine use has not been documented. Aspirin plays a key role in primary prevention strategy of cardiovascular disease in type 2 diabetes patients. With limited studies and evidence for other antiplatelet agents, their role in primary prevention has not been

Dyslipidemia is one of the major risk factors for macrovascular disease leading to CVD in

In type 2 diabetes patients with dyslipidemia, alteration in lipid distribution and platelet

Patients with type 2 diabetes with one of the following; dyslipidemia, family history of coronary heart disease, hypertension, smoking and albuminuria are at increased risk of

With limited evidence, proper justification and clinical judgments of benefit versus risk, aspirin plays a key role as antiplatelet agent in primary prevention of CVD in patients with

Patients with type 2 diabetes and dyslipidemia receiving aspirin for primary prevention strategy should be monitored for effectiveness of treatment (sign and symptoms of CVD)

Adiels, M., Westerbacka, J., Soro-Paavonen, A., Häkkinen, A.M., Vehkavaara, S., Caslake,

American Diabetes Association (2006). Standards of Medical Care in diabetes. *Diabetes Care*

American Diabetes Association (2011). Standard of Medical Care in Diabetes 2011. *Diabetes* 

Angiolillo, D.J. (2009). Antiplatelet therapy in diabetes: efficacy and limitations of current

Antithrombotic Trialists' Collaboration (2002): Collaboration meta-analysis of randomized

treatment strategies and future directions. *Diabetes Care* Vol.32, No.4, (April 2009),

trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. *BMJ Vol.*324, No.7329, (January 2002), pp. 71–86, ISSN

M.J., Packard, C., Olofsson, S.O., Yki-Järvinen, H., Taskinen, M.R. & Borén, J. (2007). Acute suppression of VLDL1 secretion rate by insulin is associated with hepatic fat content and insulin resistance. *Diabetologia* Vol.50, No.11, (November

and adverse effects (stomach pain, heartburn, nausea and bleeding tendency).

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