Let's face it: Diabetes management has been off the radar screen of most cardiologists. But the recent report of two major randomized clinical trials should reenergize research in the pathogenesis of macrovascular atherosclerotic disease in diabetes and increase our efforts in the prevention of cardiovascular sequelae of this disease.
These two trials, ACCORD (Action to Control Cardiovascular Risk in Diabetes) and ADVANCE (Action in Diabetes and Vascular Disease) (N. Engl. J. Med. 2008:358;2545-72), explored the role of intensive glucose control in the development of macrovascular and microvascular disease in type 2 diabetic patients with established cardiovascular disease or additional risk factors. Since previous clinical studies showed that hyperglycemic control modulated microvascular disease in diabetics, it seemed reasonable to further modify glucose control to prevent macrovascular disease. Both studies achieved a significant decrease in blood glucose levels, although researchers used different drug protocols to achieve their targets.
In addition to more precise insulin therapy, ACCORD used the thiazolidinedione rosiglitazone as additive therapy to achieve the target, whereas ADVANCE used the sulfonylurea gliclazide in addition to perindopril and indapamide.
Both studies were negative in their unique ways. ACCORD failed to have a positive effect on the primary outcome of a composite of nonfatal myocardial infarction and stroke in addition to cardiovascular mortality. Although the study showed a significant decrease in nonfatal myocardial infarction, this decrease was associated with an increase in all-cause mortality and morbidity due to cardiovascular disease, which led to the study's premature termination.
In contrast, ADVANCE observed a nonsignificant 10% reduction in a composite of micro- and macrovascular end points. In regard to the macrovascular end points, the major emphasis of these studies, there was no benefit observed as to nonfatal myocardial infarction, stroke, or death. The failure of the intensive glucose control strategy to limit the expression of macrovascular disease emphasizes the importance of a more aggressive approach to secondary prevention.
Diabetes continues to be a growing problem in cardiology and most certainly will increase in its incidence as our population ages and becomes more obese. The pathogenesis of the process that accelerates the deposition of cholesterol in the arterial wall in diabetes continues to elude our understanding. It is clear, however, that diabetic patients are at increased risk of atherosclerosis and coronary artery disease.
Many of the medications that have been shown to be effective in preventing the expression and progression of coronary artery disease in the general population are equally effective in diabetes patients, and are underutilized. It is estimated that fewer than 10% of diabetic patients are being treated to target for hypertension and hyperlipidemia (JAMA 2004;291:335-42). For example, ACE inhibitors were underutilized in ACCORD. And in the ADVANCE trial, fewer than 50% of the patients randomized to that study were receiving statins, and fewer than 60% were receiving aspirin. These therapies were much more widely used in ACCORD, and this increased use was associated with a lower mortality and morbidity in ACCORD than in ADVANCE.
It is possible that other targets for intervention in the diabetic patient will be developed from the further analysis of these two very important studies and subsequent research. However, it is clear from these studies that diabetic patients should be considered at high risk for the development of atherosclerosis, even if they have not expressed a clinical event. It is therefore imperative that we become more effective in instituting preventive therapies—proved effective in cardiac patients—in our diabetic patients. Even in well-organized clinical centers such as those used in these studies, these goals are difficult to achieve and are not being met.