Consideration of the derangements in platelet function, the coagulation system, and the fibrinolytic system and their contributions to exacerbation of macrovascular disease in type 2 diabetes gives rise to several therapeutic approaches. Empirical use of aspirin (160-325 mg per day in a single dose) seems appropriate in view of the high likelihood that covert CAD is present even in asymptomatic people with type 2 diabetes and the compelling evidence that prophylactic aspirin reduces the risk of heart attack when CAD is extant. Because many of the derangements contributing to a prothrombotic state in diabetes are caused by hyperglycemia, rigorous glycemic control is essential. Accordingly, the use of diet, exercise, oral hypoglycemic agents, insulin sensitizers, and if necessary insulin itself is appropriate to lower HbA1c to 7%. Because other derangements contributing to a prothrombotic state such as attenuation of fibrinolysis appear to be related to insulin resistance and hyper(pro)insulinemia, the use of insulin sensitizers as adjuncts to therapy with insulin or with other oral hypoglycemic agents is likely to be helpful.
Agents that enhance sensitivity to insulin and thereby promote glycemic control but limit hyperinsulinemia merit particular emphasis. Thiazolinediones lower elevated PAI-
1 in patients with hyperinsulinemia by attenuating insulin resistance, increasing peripheral glucose disposal, and modifying transcription of genes with protein products that are involved in carbohydrate and lipid metabolism and in fibrinolytic system activity. This class of agents exerts favorable effects on intimal medial thickness of carotid arteries in people with type 2 diabetes (134,135).
Use of metformin may attenuate abnormalities in the fibrinolytic system as well, although the primary mechanism of action of the drug differs from that of the glitazone. Metformin and its congeners decrease hepatic glucose output thereby normalizing carbohydrate and lipid metabolism and reducing requirements for insulin and lowering circulating endogenous insulin levels. Dosage should be initiated at 500 mg twice a day and gradually increased to a maximum of 2500 mg daily in three doses with meals. Optimal effects are generally seen with 1000 mg twice a day. Side effects are usually minor gastrointestinal disturbances, but lactic acidosis can be encountered particularly in patients with renal dysfunction, congestive heart failure, liver disease, or any condition predisposing to metabolic acidosis including diabetic ketoacidosis or excessive consumption of alcohol. Metformin should be discontinued temporarily when contrast agents are used (e.g., coronary angiography) to avoid lactic acidosis. In contrast to the glitazone, metformin can produce hypoglycemia, particularly when it is used with sulfonylureas.
The use of antiplatelet GP Ilb/IIIa antagonists appears to be particularly beneficial in patients with symptomatic CAD and type 2 diabetes. The most cogent argument can be made for their use in patients who will be undergoing PCI. In one study of patients with diabetes who had sustained an ACS, the use of tirofiban reduced the incidence of the combined end-point of death or MI from 15.5% to 4.7% (136). The use of abciximab in patients with diabetes undergoing PCI reduced the 1-year mortality from 4.5% to 2.5% (137). GP IIb/IIIa inhibitors should be used for the treatment of people with diabetes with ACS including unstable angina and non-ST-segment elevation acute MI, especially in association with PCI.
Several complications and concomitants of diabetes can exacerbate a prothrombotic state and accelerate vascular disease. Thus, hypertriglyceridemia, hypertension, and hyperglycemia must be ameliorated. Lipid-lowering drugs should be used vigorously as is evident from results from studies such as the CARE trial in which the incidence of CAD was reduced by 27% in diabetic subjects to an extent comparable to that in nondiabetic subjects by administration of pravastatin over 5 years of follow-up (138).
Hypertension should be treated vigorously, generally with angiotensin-converting enzyme inhibitors because of the demonstrated reduction of progression of renal disease accompanying their use. An alternative may be angiotensin receptor blocking agents. Despite the ominous portent of macrovascular disease in type 2 diabetes, nephropathy continues to be a dominant life-threatening complication with an extraordinarily high incidence. Its occurrence is clearly related to hyperglycemia and may contribute to a prothrombotic state and acceleration of macrovascular disease through diverse mechanisms. Accordingly, rigorous glycemic control is essential.
Lifestyle modifications including implementation of a regular exercise program, reduction of obesity through dietary measures, and avoidance or cessation of cigarette smoking should be implemented to reduce the intensity of a prothrombotic state and the progression of macrovascular disease. Vitamin B6 (1.7 mg per day) and folic acid (400 ^g of dietary or 200 ^g of supplemental folic acid per day) in recommended daily allowance (RDA) doses appear to be appropriate particularly because elevated homocysteine (139)
and oxidative stress (140) associated with accelerated atherosclerosis are common in people with diabetes (5). Elevated concentrations of homocysteine can be reduced readily with these doses of folic acid and vitamin B6 in patients at risk of CAD whose homocysteine levels are in the upper percentiles of the normal range or only mildly elevated above normal. If concentrations of homocysteine are not normalized (to 14 pM) the likelihood of the subject being heterozygous for cystathionine ^-synthase or homozygous for the thermolabile variant of the product of the methylene tetrahydrofolate reductase gene (MTHFR) is high in which case, 1 mg or more of folate per day may be needed to normalize concentrations of homocysteine. As a precaution, inclusion in supplements of vitamin B12 (1.2 pg per day, the RDA) is advisable when folic acid supplements are used to avoid potential neurological damage that can be induced by folate in the presence of occult B12 deficiency. Vitamin E (400 IU per day) has been more clearly implicated than vitamin C in reducing risk associated with oxidative stress although neither has been proved to be beneficial. It appears likely that increasing use of insulin sensitizers will retard the evolution of macrovascular disease as demonstrated already in the preliminary results of studies documenting favorable changes in carotid intimal-medial thickness accompanying their use (134,135).
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