Managed Care - October 2008 - (Page 40) end-stage renal disease, affecting up to 40 percent of people with diabetes. Neuropathy as a consequence of diabetes can lead to impaired sensation, delayed digestion, or carpal tunnel syndrome; it contributes significantly to lower-limb amputations (American Diabetes Association 2006, National Diabetes Information Clearinghouse 2007). Recent evidence suggests that the abnormal metabolic environment of hyperglycemia represents the primary cause for the development of both microvascular and macrovascular complications (Brownlee 2005, Brownlee 2001). Genetic factors contribute to individuals’ susceptibility to the metabolic milieu characterized by insulin resistance, hyperglycemia, and hyperinsulinemia. Factors such as hypertension, diet, smoking, and hyperlipidemia can increase or decrease the risk of developing complications. Some investigators believe that during the early stages of insulin resistance and impaired glucose tolerance, there is only minimal tissue damage (i.e., reduced nerve conduction velocity, microalbuminuria) and rigorous control of glucose levels may inhibit further deterioration. However, after prolonged duration and intensity of the abnormal metabolic environment, irreversible tissue damage ensues, regardless of maintenance of euglycemia. Previously, discussions of the clinical consequences of diabetes focused more on microvascular complications. As our understanding of the metabolic syndrome (insulin resistance syndrome) increases, we recognize that macrovascular complications may present even before patients are actually diagnosed with diabetes. As the incidence of diabetes approaches epidemic proportions, and the disease appears in younger individuals, the clinical impact of these conditions becomes markedly amplified. Clinicians would be well served, then, to use a rational, systematic approach to treating diabetes and associated conditions and to treat earlier and more aggressively. TREATMENT: IT’S NOT ONE SIZE FITS ALL Table 1 shows the American Diabetes Association’s (ADA) recommended glycemic goals for adults with diabetes. Algorithms generated by the ADA propose routes to guide physicians’ treatment decisions to achieve these goals (see figure 2). However, the previous discussion on the pathophysiology of metabolic syndrome and type 2 diabetes underscores the importance of not only working toward euglycemia but treating the disorders mediating the development of macrovascular and microvascular complications, including dyslipidemia and hypertension. To have a truly significant impact on slowing the development of vascular disease, a more individualized approach to treatment may be necessary. The importance of lifestyle modification cannot be overemphasized. In addition, a more complete TABLE 1 ADA recommended levels for adults with type 2 diabetes Glycemic Control A1C Preprandial capillary plasma glucose Peak postpreprandial capillary plasma glucose Blood pressure Lipids LDL Triglycerides HDL <7.0% 90–130 mg/dL <180 mg/dL <130/80 mm Hg <100 mg/dL 40 mg/dL understanding of the available drugs could help physicians select therapies providing even more patient benefits. Diabetes drugs vary considerably with regard to their effects on lipids and β-cells, impact on cardiovascular outcomes, and effect on weight. Consider the insulin secretagogues. Sulfonylureas and the glinides stimulate pancreatic β-cells to increase insulin secretion. The sulfonylureas are older agents, relatively inexpensive, and of comparable effectiveness with regard to lowering blood sugar. Side effects include hypoglycemia, weight gain, and, potentially, sulfa allergy (Goke 2000). By their very mechanism of action, these agents promote hyperinsulinemia, which further contributes to cardiovascular risk in already at-risk patients. In addition, use of these agents seems to hasten β-cell failure in type 2 diabetes. Increased βcell apoptosis has been noted (Maedler 2005). A recent report suggests that sulfonlyureas may also increase cancer incidence (Bowker 2006). Now let’s look at the thiazolidinediones, particularly in terms of cardiovascular safety. Nissen, et al, published a meta-analysis of studies of rosiglitazone which suggested that rosiglitazone use was associated with a significant increase in the risk of myocardial infarction and a borderline-significant increase in the risk of death from cardiovascular causes (Nissen 2007). A meta-analysis by Singh, et al, corroborated these findings, noting that the use of rosiglitazone for at least one year is associated with a significantly increased risk of myocardial infarction and heart failure, although these authors did not find a significantly increased risk of cardiovascular mortality (Singh 2007). A different meta-analysis reviewed studies involving over 16,000 individuals to evaluate the effects of pioglitazone on ischemic cardiovascular events (Lincoff 2007). Unlike rosiglitazone, pioglitazone was associated with a significantly lower risk 40 MANAGED CARE / OCTOBER 2008
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