Among patients with type 2 diabetes and stable ischemic heart disease receiving intensive medical therapy, there was little difference between insulin sensitization and insulin provision with respect to rates of death and cardiovascular events at 5 years. Likewise, a strategy of prompt coronary revascularization with the procedure most appropriate for the individual patient and a strategy of medical therapy led to similar clinical outcomes. Prompt revascularization significantly reduced major cardiovascular events, as compared with intensive medical therapy, among patients who were selected to undergo CABG but not among those who were selected to undergo PCI.
Our study was designed to compare coronary revascularization with intensive medical therapy, not to compare CABG with PCI. Patients who were selected to undergo CABG were expected to have higher event rates; indeed, among patients who were assigned to the medical-therapy group in the CABG stratum, the 5-year mortality (16.4%) was much higher than that among patients assigned to medical therapy in the PCI stratum (10.2%).
The study was designed to reflect how physicians might confront treatment decisions in practice. Our findings suggest that patients who have diabetes, evidence of myocardial ischemia, and extensive multivessel disease would benefit from prompt surgical revascularization mainly because of a lower rate of nonfatal myocardial infarction. However, for the many patients with type 2 diabetes who have less extensive coronary disease and for whom PCI is judged to be more appropriate, prompt revascularization did not reduce the risk of cardiovascular events, as compared with medical therapy. Approximately one third of patients in the PCI stratum who were assigned to undergo revascularization received a drug-eluting stent, but since these devices have not been shown to reduce rates of death or major cardiovascular events,27
their use probably did not affect the results.
It is important to note that all the patients who were assigned to receive medical therapy underwent careful clinical monitoring, and 42.1% had changes in the clinical course that called for later revascularization during 5 years of follow-up. In clinical practice, the initial treatment strategy for a patient with diabetes and coronary disease rarely remains constant over a 5-year period. The fact that most patients in the medical-therapy group did not require coronary revascularization during the 5-year period suggests that many patients may be safely treated with intensive medical therapy.
Our two-by-two factorial design allowed further comparisons between combinations of strategies. Among patients for whom CABG was selected as the intended method of revascularization, the combination of prompt revascularization and an insulin-sensitization strategy was associated with a significantly lower rate of major cardiovascular events than any of the other three treatment combination groups. Although previous studies have shown a beneficial effect on cardiovascular outcomes associated with the use of insulin sensitization with thiazolidinediones9,28,29
our results cannot distinguish between the effect of either agent or the combination.
The strategies for glycemic control that we tested were not implemented at the time of initial diagnosis of diabetes, and there was inevitably less than complete differentiation of treatment regimens. The treatment regimens in our study reflect what is clinically possible for patients with established type 2 diabetes. Intensification of medical therapy and consistent monitoring led to improved control of cardiac risk factors across the board. Although only 28.4% of patients simultaneously achieved all three protocol targets at 3 years, the rates of control attained in this trial were much better than the rates recorded for community care31,32
and similar to those reported in other trials.33,34
The mean follow-up glycated hemoglobin values in the insulin-sensitization group and the insulin-provision group were close to the target level of 7.0% but differed significantly from each other. The mean difference of less than 0.5% in glycated hemoglobin levels between the two glycemic-control strategies in our study was less than the mean difference of 1.6% in the Veterans Affairs Diabetes Trial (VADT) (ClinicalTrials.gov number, NCT00032487),33
the difference of 1.1% in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (NCT00000620),35
and the difference of 0.6% in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial (NCT00145925).34
Since none of these trials that compared different glycemic-control targets showed a significant reduction in cardiovascular events, it is unlikely that our results were due solely to differences in the level of glycemic control.
In our study, plasma insulin levels were consistently lower over time in patients in the insulin-sensitization group (median, 6.3 μU per milliliter) than in those in the insulin-provision group (median, 10.0 μU per milliliter), a finding that is consistent with the mechanisms of action of metformin and thiazolidinediones. Despite the need to administer insulin or sulfonylureas to some patients, patients in the insulin-sensitization group were maintained at or very near the target level for glycated hemoglobin. Moreover, the insulin-sensitization strategy was associated with fewer severe hypoglycemic episodes, less weight gain, and higher HDL levels than those in the insulin-provision strategy. These data may suggest that insulin sensitization is preferable for patients with type 2 diabetes and coronary disease.
Like all randomized clinical trials, our study was limited in terms of the generalizability of results to all patients with type 2 diabetes and coronary disease. Furthermore, confidence intervals for the overall between-group differences were within 3% for the rate of death and 6% for the rate of major cardiovascular events; smaller treatment effects could have been missed.
In summary, a strategy of prompt coronary revascularization in patients who had been treated with intensive medical therapy for diabetes and stable ischemic disease did not significantly reduce the rate of death from any cause or of major cardiovascular events. Insulin sensitization and insulin provision also had similar cardiovascular outcomes during a 5-year period. Among patients for whom CABG was deemed to be the appropriate treatment, prompt revascularization reduced the rate of major cardiovascular events, as compared with medical therapy, particularly among patients who were assigned to receive insulin sensitization. In the PCI stratum, however, revascularization did not reduce the rate of death or major cardiovascular events when added to medical therapy.