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The glucose – CVD connection: the search for the missing link
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As 2008 came to a close, yet another publication appeared as the product of the ongoing search for a linkage between intensive glycemic control and reductions, if any, in cardiovascular endpoints.
The VA Diabetes Trial of 1,800 patients randomized to intensive management with multiple strategies designed to reduce HbA1c levels below 7% as compared to usual care, which perpetuated poor control of approximately HbA1c levels of 8.5% were compared with regard to macrovascular and microvascular endpoints.
As with other, larger trials recently published regarding similar endpoints, there was no clinical benefit to intensive control in this population of patients. In this study, patients had greater than 11 years of generally poor glycemic control prior to randomization and a high rate of cigarette smoking. Their LDL levels were not optimal prior to randomization either. On trial, LDL levels declined by 25%, substantial numbers of patients (approximately 80%) stopped smoking and HbA1c levels decreased by 1.5% to less than 7% on treatment. Because of the multiplicity of interventions, the actual CV event rate was much lower than expected in both the control and the glycemic intervention groups. Although there was an 11% reduction in events in the intensive control cohort, this was not sufficient to achieve statistical significance. These findings are highly similar to the experience of the glucose control arm of ACCORD, which also saw fewer than predicted events and no substantial benefit to intensive intervention.
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At the close of this cycle of research studies designed to clarify the lack of efficacy of glycemic control on CHD reduction noted in the UKPDS, we are no further along than before we started. Perhaps, we are worse off. Clearly, we are seeing much lower rates of CHD in populations of patients with type 2 diabetes. This no doubt reflects diffusion of validated strategies for CHD risk reduction including aggressive LDL reduction, antiplatelet therapies, better hypertension management and effective stop smoking campaigns. Glycemic control may be unable to show a meaningful benefit owing to the extreme reduction in baseline rates of events. Thus, in such a setting, 18,000 rather than 1,800 patients may have been required to see adequate treatment benefit. On the other hand, after 11 years of poor glycemic control, high rates of tobacco abuse, hypertension and lifestyle inadequacies may have permanently obscured the possibility of discerning any link between glucose and atherosclerosis.
Despite the strong epidemiologic evidence for linkage between glycemic control and CHD risk in patients with diabetes, this consistent lack of interventional benefit of glycemic control is disturbing at best. Thus, it becomes difficult to aggressively pursue control in patients who may have adverse events from such strategies, since there appears to be no offsetting gains with respect to the risk of end stage complications.
Five major trials have thus far failed to demonstrate benefits with regard to glycemic control and CHD risk reduction including the Kumomoto Study, UKPDS, ACCORD, ADVANCE and now VADT. Five trials should be enough to conclude that no persuasive linkage exists between glucose and CHD risk in patients with type 2 diabetes. Regardless of logic, regardless of epidemiology, no link seems evident. Yet, these more recent trials do have benefits to be seen, if only we seek them.
In every one of these trials, event rates have clearly been much lower than historical or expected or both. Widespread implementation of effective CHD risk reduction strategies has eliminated the bulk of the CHD excess in populations of patients with type 2 diabetes. We have therefore succeeded in our primary goal, namely to reduce CHD in patients with type 2 diabetes. We should move on to secondary goals, such as microvascular risk reduction. This has always been an issue in diabetes management, but only recently has been understood to be the proper focus of diabetes management. To be sure, the overweighting of CHD risk reduction was nothing if not an overreaction to the prior failure to include or recognize excess CHD as a major complication of the Diabetic State. But, perhaps this is an idea whose time has passed. We have seen this complication and recognized how to deal with it.
It is time to move on, back to the problem of the microvascular complications and the need for comprehensive patient management strategies which deal with all of the complications seen in patients with diabetes, not merely those in favor at the moment.
Alan J. Garber, MD, PhD, is Professor in the Departments of Medicine, Biochemistry and Molecular Biology, and Cellular and Molecular Biology at Baylor College of Medicine in Houston, and is Chief Medical Editor of Endocrine Today.