Role of Insulin Secretagogues and Insulin Sensitizing Agents in the Prevention of Cardiovascular Disease in Patients who have Diabetes

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aDepartment of Medicine, Section of Endocrinology, Tulane University Medical Center, SL-53, 1430 Tulane Avenue, New Orleans, LA 70112-2699, USA bDepartment of Medicine, Veterans Affairs Medical Center, 1601 Perdido Street, New Orleans, LA 70112, USA

Cardiovascular disease is the leading cause of death among patients who have diabetes mellitus. Patients who have diabetes mellitus have a greatly increased relative risk of cardiovascular disease when compared with patients who do not have diabetes mellitus [1]. Furthermore, in patients who have established cardiovascular disease, the rate of subsequent cardiovascular events is significantly higher than in individuals who do not have diabetes mellitus [2] and is associated with greatly increased morbidity and mortality. Epidemiologic studies showed that diabetic patients are more prone to develop complications following cardiovascular events [3]. Moreover, diabetic patients who have ischemic heart disease have a substantially worse outcome after coronary interventional procedures compared with nondiabetic patients [4]. The basis for these differences in outcome remained unclear. In most animal studies, diabetic myocardium demonstrates an enhanced sensitivity to the detrimental effect of ischemia/reperfusion injury and it generally is believed that diabetes mellitus is less tolerant to such injury [3]. Recent advances in invasive cardiology and medical therapy have led to a significant reduction in cardiovascular mortality in nondiabetic men and women; however, the reduction in cardiovascular mortality in men who

* Corresponding author. Department of Medicine, Section of Endocrinology, Tulane University Medical Center, SL-53, 1430 Tulane Avenue, New Orleans, LA 70112-2699.

E-mail address: [email protected] (V.A. Fonseca).

have diabetes mellitus has been modest and not statistically significant [5], whereas mortality rates increased during a 10-year period in women who had diabetes mellitus.

Diabetes is a complex disease. At least two underlying defects have been postulated in the pathogenesis of this condition. First, b-cell dysfunction and failure that lead to elevated glucose levels result in oxidative stress that causes increased cardiovascular morbidity. Second, insulin resistance, which is associated with endothelial dysfunction, inflammation, and abnormal fibrinolysis contributes to cardiovascular disease [6,7]. Most patients have both defects and the defects frequently are interrelated, in that hyperglycemia itself can lead to insulin resistance and insulin resistance can cause b-cell dysfunction. Fig. 1 illustrates these interactions and outlines a pathway between these defects and cardiovascular disease.

Few long-term studies that compared the effects of secretagogues with sensitizers on cardiovascular outcomes have been conducted. Of particular importance is the United Kingdom Prevention of Diabetes Study (UKPDS), which demonstrated that in obese patients, a weak sensitizer like metformin may be better than a secretagogue in preventing myocardial infarction and cardiovascular mortality.

In the UKPDS, patients who had type 2 diabetes mellitus were randomized to intensive (medication) or conventional (diet) treatment and were observed for approximately 10 years. The group that was assigned to intensive treatment

Fig. 1. Pathogenesis of cardiovascular disease in diabetes mellitus.

underwent a subsequent randomization to primary therapy with sulfonylurea or insulin. In addition, obese patients were randomized to metformin or placebo. When compared with conventional therapy, intensive treatment was associated with a decreased risk of predominantly microvascular complications, including a 12% reduction in any diabetes-related end point (P = 0.03) and a 25% reduction in all microvascular end points (P < 0.001). There was no significant effect on diabetes-related death or on all-cause mortality, however, and there only was a trend toward a small effect (—16%) on the risk of myocardial infarction (P = 0.05) [8]. Overall, there were no significant differences between subjects who were treated with sulfonylurea and those who were treated with insulin. Improved glycemic control from sulfonylureas alone is not enough to decrease macrovascular risk. In contrast, obese patients who were randomized to metformin had a reduction in myocardial infarction and cardiovascular mortality. This finding has started a controversial debate about the relative benefits of sensitizers and secretagogues in preventing cardiovascular disease and cardiovascular events.

This article examines the evidence in favor or against choosing treatment with insulin secreta-gogues or sensitizers as the preferred way to prevent cardiovascular events. It should be emphasized that most patients eventually will be treated with a combination of therapies; therefore, much of the discussion may not be relevant. Conversely, combination of two sensitizers may have added effects [9,10]. Also, retrospective data suggest that a combination of sulfonylurea and metformin may be associated with increased cardiovascular events [11]. Nevertheless, it is important to recognize the relative value of these different agents as we choose complex therapeutic regimens.

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