Cardiovascular disease constitutes the major cause of morbidity and mortality in patients with T2DM, accounting for at least 65% of deaths in these patients.
23 In the United Kingdom Prospective Diabetes Study (UKPDS, consisting of patients with T2DM) and the Diabetes Control and Complications Trial (DCCT, consisting of patients with type 1 diabetes mellitus), evidence was found that intensive glycemic control prevents the development and progression of microvascular complications in patients with diabetes mellitus. However, whether intensive glucose lowering also prevents macrovascular disease and major cardiovascular events remains unclear.
24
Three large-scale cardiovascular outcome trials evaluated the effects of intensive glucose control, rather than a specific therapeutic regimen, on macrovascular outcomes. These 3 trials were the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,
25 the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial,
26 and the Veterans Affairs Diabetes Trial (VADT).
27
The ACCORD Study Group
25 compared the effect of an intensive glucose-lowering strategy (ie, target glycosylated hemoglobin [HbA
1c] level, <6%) to that of a standard glucose-lowering strategy (ie, target HbA
1c level, 7.0%-7.9%) on cardiovascular events in patients with T2DM who had either established CVD or additional CVD risk factors.
25 A total of 10,251 patients (mean age, 62.2 y) with a median HbA
1c level of 8.1% were enrolled in the study. Of these enrolled patients, 38% were women, and 35% had a previous cardiovascular event.
Compared to the standard glucose-lowering group, the intensive glucose-lowering group in the ACCORD trial
25 had a lower mean HbA
1c level (6.4% intensive vs 7.5% standard) and a more rapid rate of HbA
1c reduction in the first 4 months of treatment (-1.4% intensive vs -0.6% standard). Hypoglycemia requiring assistance and weight gain of more than 10 kg were also more frequent in the intensive glucose-lowering group (
P<.001).
25 The ACCORD trial was discontinued after a 3.5-year median follow-up because of a statistically significant increase in all-cause mortality in the intensive glucose-lowering study group (hazard ratio, 1.22; 95% confidence interval, 1.01-1.46;
P=.04).
Similar to ACCORD, the ADVANCE trial
26 evaluated the effect of glycemic control on vascular outcomes in patients with T2DM. A total of 11,140 patients with T2DM were randomly assigned to receive either standard glucose control (with target HbA
1c defined on the basis of local guidelines) or intensive glucose control (target HbA
1c level, ≤6.5%). After a median follow-up of 5 years, the mean HbA
1c level was lower in the intensive glucose control group than in the standard glucose control group (6.5% intensive vs 7.3% standard,
P<.001). The incidence of combined major macrovascular and microvascular events was reduced in patients receiving intensive glucose control compared to patients receiving standard treatment (18.1% intensive vs 20.0% standard,
P=.01). This reduction was primarily the result of a statistically significant reduction in major microvascular events with intensive treatment (10.9% intensive vs 9.4% standard,
P=.01).
The ADVANCE trial
26 found no statistically significant differences from intensive vs standard glucose control on major macrovascular events, on death from CVD, or on death from any cause. Severe hypoglycemia, though uncommon in both groups, was more common in the intensive-control group than in the standard-control group (2.7% intensive vs 1.5% standard;
P<.001).
26
The primary goal of the VADT
27 was to compare the effects of intensive and standard glucose control on cardiovascular events in patients with long-standing T2DM. A total of 1719 military veterans (mean age, 60.4 y) whose diabetes mellitus was poorly controlled (mean baseline HbA
1c level, 9.4%) on current treatment were enrolled in the study. The mean length of time since T2DM diagnosis was 11.5 years, and 40% of patients had previously had a cardiovascular event. Results showed that the mean HbA
1c level was reduced to 6.9% in the intensive-treatment group compared to 8.4% in the standard-treatment group. Over a median follow-up of 5.6 years, there was no statistically significant effect of intensive glucose control on macrovascular or microvascular outcomes compared to standard glucose control.
27
Interestingly, patients in ACCORD,
25 ADVANCE,
26 and VADT
27 all had established T2DM (mean duration, 8-11 y) and either known CVD or multiple cardiovascular risk factors. Subset analysis of the 3 trials suggested benefits of intensive glycemic control on CVD in patients with shorter duration of T2DM, lower baseline HbA
1c level, or absence of known CVD.
28
Long-term epidemiologic follow-up of some landmark trials provides evidence that intensive glycemic control early in the course of T2DM may yield CVD benefits.
29,30 Intensive glycemic control initiated in relatively young patients free of CVD risk factors was associated with a 57% reduction in major CVD outcomes in the DCCT-Epidemiology of Diabetes Interventions and Complications (EDIC) trial.
29 However, the CVD benefit observed in DCCT-EDIC required 9 years of follow-up beyond the end of the trial to reach a level of statistical significance.
29 In a 10-year follow-up of the UKPDS, statistically significant long-term reductions in myocardial infarction and all-cause mortality were observed in patients who had been randomly assigned to intensive glycemic control compared with patients assigned to conventional glycemic control.
30
Skyler et al
28 proposed, “as is the case with microvascular complications, it may be that glycemic control plays a greater role before macrovascular disease is well developed and a minimal or no role when it is advanced.”
28 It is also apparent that it will take much longer to obtain macrovascular benefit from glucose control than it takes to obtain microvascular benefit from glucose control.
Results of these large, randomized trials suggest that intensive glycemic targets of 6% or less may be too aggressive. Current guidelines by the American Diabetes Association (ADA), the American Heart Association (AHA), and the American College of Cardiology (ACC)
28—based on evidence obtained from ACCORD,
25 ADVANCE,
26 and VADT
27—reaffirm an HbA
1c target goal of less than 7% for patients with T2DM. However, in the joint ADA/AHA/ACC position/scientific statement,
28 the need for additional clarification regarding glycemic control was highlighted, and the following recommendations were provided:
This statement
28 supports the view that treatment should be individualized for patients with T2DM—with more aggressive, earlier HbA
1c targets potentially appropriate for younger patients with diabetes mellitus, and standard HbA
1c goals appropriate for patients with established T2DM in whom CVD is known or likely to be present.
20