The Role of Glycemia Management in the Prevention of Cardiovascular DiseaseStarting Over?

The DCCT (Diabetes Control and Complications Trial) for type 1 diabetes (1) and the UKPDS (United Kingdom Prospective Diabetes Study) for type 2 diabetes (2) seemed to lay to rest the contentious debate over the relationship between glycemic control and the long-term complications of diabetes mellitus. These randomized trials of intensive therapy to achieve near-normal glucose control established the benefits of intensive therapy over conventional (at the time) therapy on the microvascular and neurologic complications that epidemiologic studies had shown to be associated with the level of chronic glycemia (3, 4). Neither trial established that intensive therapy reduced cardiovascular disease (CVD), a major cause of morbidity and mortality in diabetes, possibly because of the low number of events (1, 2, 5). Subsequent observational follow-up data demonstrated 57% and 15% reductions in major CVD events in the DCCT and UKPDS, respectively, on the basis of intention-to-treat analyses of original treatment assignment (6, 7). The more profound effect of intensive therapy in the DCCT than in the UKPDS cohort was probably the result of greater separation in hemoglobin A1c (HbA1c) levels in the DCCT than in the UKPDS and the more complex CVD risk background of type 2 diabetes, with its associated hypertension, dyslipidemia, obesity, and older age (8). The rate of CVD was about 4-fold higher in the UKPDS population than in the DCCT population, both with about 25 years of diabetes duration (6, 7). Given the apparent long-term benefit on CVD of the intensive therapies that achieved mean HbA1c levels of about 7%, compared with levels in the conventional treatment groups of about 9% in the DCCT and 7.9% in the UKPDS, why do we remain uncertain about the role of intensive glycemic therapy in the prevention of CVD? The uncertainty originates in 2 observations and the results of several recent trials. First, epidemiologic studies have demonstrated an association between HbA1c levels in the subdiabetic range and an increased risk for CVD (9, 10). Second, even after adjustment for conventional CVD risk factors, diabetes continues to be associated with excess risk for CVD (11). Consequently, investigators wondered whether even more stringent glycemic control would reduce CVD. Three large randomized, controlled trials investigated whether intensive therapy aimed at maintaining HbA1c levels less than 6.0% (the ACCORD [Action to Control Cardiovascular Disease in Diabetes] study [12] and the VADT [Veterans Affairs Diabetes Trial] [13]) or 6.5% or less (the ADVANCE [Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation] trial [14]) would reduce major CVD events compared with interventions aimed at higher levels. The ACCORD study employed an algorithm in the intensive treatment group that used as many as 5 classes of glucose-lowering medications (12); the VADT used rosiglitazone plus metformin or sulfonylurea, depending on body mass index, with insulin added as needed (13); and the ADVANCE trial used a sulfonylurea-based therapy with other medications as needed (14). Each trial used different medication profiles in the active and control groups, potentially confounding the observed effects of glucose control on CVD outcomes. For example, in the ACCORD study, more patients in the intensive treatment group than in the conventional treatment group were treated with rosiglitazone (91% vs. 58%) (12). In the ADVANCE trial, 91% of patients in the intensive treatment group received gliclazide, compared with 2% in the conventional treatment group (14). All 3 studies failed to show reduction in aggregate CVD outcomes with intensive glycemic management; however, a subsequent meta-analysis that included the 3 trials and 2 other studies showed a 15% decrease in major CVD outcomes (15). Of note, the ACCORD study was stopped ahead of schedule because of an increase in all-cause (hazard ratio, 1.22) and CVD (hazard ratio, 1.35) mortality in the intensive treatment group (both P< 0.050) (12). In the absence of proof that achieving HbA1c levels of 6.5% or less improves CVD outcomes, recent observational studiesincluding Greenfield and colleagues' 5-year cohort study in this issue (16), 2 meta-analyses (15, 17), and 2 guidelines (18, 19)aim to define appropriate treatment goals for patients with type 2 diabetes. Greenfield and colleagues caution against causal inferences but describe an apparent benefit from HbA1c levels of 6.5% or less or 7.0% or less on incident CVD, albeit only in the subcohort of their Italian practicebased population with low to moderate baseline comorbidity. The lower levels of comorbidity were based in part on less prevalent CVD at baseline and, not surprisingly, were accompanied by a lower incidence of CVD. The subcohort with low to moderate comorbidity was also younger and less heavy and had a shorter duration of diabetes than the subcohort with high comorbidity. The study, which shows an association between glycemia and CVD, is reminiscent of the earlier epidemiologic articles that led to the current crop of clinical trials. The somewhat novel finding in the study is the influence of comorbidity on the effect of lower versus higher HbA1c levels on incident CVD. However, this finding was present only when comorbidity was defined as a dichotomous variable. Analyses based on tertiles of baseline comorbidity did not establish a dose effect of comorbidity; only the middle tertile showed a significant difference in the relationship between HbA1c levels and CVD. The absence of data on concurrent therapies is a major shortcoming, because more aggressive therapy for hypertension or dyslipidemia in the group with higher comorbidity could have decreased the relative effect of glucose control. Efficient trial design requires persons at high risk for the study outcome. A history of CVD provides the highest risk state for future CVD events, and approximately one third of the ACCORD, ADVANCE, and VADT populations had a history of CVD. If we take Greenfield and colleagues' conclusions at face value, future studies should include patients with few comorbid conditions and, consequently, lower CVD risk than in previous studies. Moreover, the demonstrated benefits of more aggressive treatment of hypercholesterolemia and hypertension will probably continue to lower CVD event rates. Therefore, future trials would need to dwarf previous studies. For example, the ACCORD study (12)which cost in excess of $165000000 and included 10000 volunteershad 89% power to detect a 15% difference in outcomes between the 2 treatment groups, on the basis of an assumed primary outcome rate of 2.9% per year in the conventional treatment group (the actual rate was 2.3% per year). If future studies include a relatively younger population with lower baseline morbidity, they might have baseline CVD rates that approach 1% per year. Thus, a trial designed to detect the 15% decrease in aggregate CVD suggested in meta-analysis (15) and a hazard rate of 1.0 aggregate CVD events per 100 patient-years would require 30000 volunteers followed for 6 years. Where do we go from here? With more than 100000 patient-years of clinical trial experience to date and no conclusive data to suggest that achieving an HbA1c level of 6.5% or less improves CVD outcomes, future studies are unlikely to demonstrate more than a modest benefit. We must carefully consider whether the putative and modest benefit of achieving an HbA1c level of 6.0% or 6.5%, compared with that of a level 1% higher, is worth exploring in a study that would consume far more resources than previous efforts. Even if lowering HbA1c level much below 7% proves to be effective in patients with type 2 diabetes and low comorbidity, it is unlikely to be cost-effective. Meanwhile, clinicians can be confident that aiming for an HbA1c level less than 7% is justified by the strong evidence that it prevents or delays progression of microvascular and neurologic complications and seems to reduce CVD in follow-up studies from the DCCT and UKPDS.