Diabetes is defined by its association with hyperglycemia-specific microvascular complications; however, it also imparts a two- to fourfold risk of cardiovascular disease (CVD). Although microvascular complications can lead to significant morbidity and premature mortality, by far the greatest cause of death in people with diabetes is CVD. Results from randomized controlled trials have demonstrated conclusively that the risk of microvascular complications can be reduced by intensive glycemic control in patients with type 1 (1,2) and type 2 diabetes (3–5). In the Diabetes Control and Complications Trial (DCCT), there was an ∼60% reduction in development or progression of diabetic retinopathy, nephropathy, and neuropathy between the intensively treated group (goal A1C 9%) to good control (e.g., A1C <7%). All three trials were carried out in participants with established diabetes (mean duration 8–11 years) and either known CVD or multiple risk factors, suggesting the presence of established atherosclerosis. Subset analyses of the three trials suggested a significant benefit of intensive glycemic control on CVD in participants with shorter duration of diabetes, lower A1C at entry, and/or or absence of known CVD. The finding of the DCCT follow-up study, that intensive glycemic control initiated in relatively young participants free of CVD risk factors was associated with a 57% reduction in major CVD outcomes, supports the above hypothesis. Of note, the benefit on CVD in the DCCT-EDIC (Epidemiology of Diabetes Interventions and Complications) required 9 years of follow-up beyond the end of the DCCT to become statistically significant. A recent report (13) of 10 years of follow-up of the UKPDS cohort describes, for the participants originally randomized to intensive glycemic control compared with those randomized to conventional glycemic control, long-term reductions in MI (15% with sulfonylurea or insulin as initial pharmacotherapy and 33% with metformin as initial pharmacotherapy, both statistically significant) and in all-cause mortality (13 and 27%, respectively, both statistically significant). These findings support the hypothesis that glycemic control early in the course of type 2 diabetes may have CVD benefit. 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. People with type 1 diabetes, in whom insulin resistance does not predominate, tend to have lower rates of coexisting obesity, hypertension, and dyslipidemia than those with type 2 diabetes and yet are also at high lifetime risk of CVD (14). It is possible that CVD is more strongly glycemia mediated in type 1 diabetes and that intervening on glycemia would ameliorate CVD to a greater extent in type 1 than in type 2 diabetes. Finally, the inability of ACCORD, ADVANCE, and VADT to demonstrate significant reduction of CVD with intensive glycemic control could also suggest that current strategies for treating hyperglycemia in patients with more advanced type 2 diabetes may have counter-balancing consequences for CVD (such as hypoglycemia, weight gain, or other metabolic changes). Results of long-term CVD outcome trials utilizing specific antihyperglycemic drugs, intensive lifestyle therapy (such as the Look AHEAD [Action for Health in Diabetes] study), bariatric surgery, or other emerging therapies may shed light on this issue. 4. What are the implications of these findings for clinical care? The benefits of intensive glycemic control on microvascular and neuropathic complications are well established for both type 1 and type 2 diabetes. The ADVANCE trial has added to that evidence base by demonstrating a significant reduction in the risk of new or worsening albuminuria when median A1C was lowered to 6.3% compared with standard glycemic control achieving an A1C of 7.0%. The lack of significant reduction in CVD events with intensive glycemic control in ACCORD, ADVANCE, and VADT should not lead clinicians to abandon the general target of an A1C <7.0% and thereby discount the benefit of good control on serious and debilitating microvascular complications. The ADA's Standards of Medical Care in Diabetes (6) and the AHA and ADA's scientific statement on prevention (15) advocate controlling nonglycemic risk factors (through blood pressure control, lipid lowering with statin therapy, aspirin therapy, and lifestyle modifications) as the primary strategies for reducing the burden of CVD in people with diabetes. The lower-than-predicted CVD rates in ACCORD, ADVANCE, and VADT, as well as the recent long-term follow-up of the Steno-2 multiple risk factor intervention (16), provide strong confirmation of the concept that comprehensive care for diabetes involves treatment of all vascular risk factors—not just hyperglycemia. The evidence for a cardiovascular benefit of intensive glycemic control remains strongest for those with type 1 diabetes. However, subset analyses of ACCORD, ADVANCE, and VADT suggest the hypothesis that patients with shorter duration of type 2 diabetes and without established atherosclerosis might reap cardiovascular benefit from intensive glycemic control. Conversely, it is possible that potential risks of intensive glycemic control may outweigh its benefits in other patients, such as those with a very long duration of diabetes, known history of severe hypoglycemia, advanced atherosclerosis, and advanced age/frailty. Certainly, providers should be vigilant in preventing severe hypoglycemia in patients with advanced disease and should not aggressively attempt to achieve near-normal A1C levels in patients in whom such a target cannot be reasonably easily and safely achieved. The evidence obtained from ACCORD, ADVANCE, and VADT does not suggest the need for major changes in glycemic control targets but, rather, additional clarification of the language that has consistently stressed individualization: Microvascular disease: Lowering A1C to below or around 7% has been shown to reduce microvascular and neuropathic complications of type 1 and type 2 diabetes. Therefore, the A1C goal for nonpregnant adults in general is <7%. ADA, A-level recommendation; ACC/AHA, class I recommendation (level of evidence A). Macrovascular disease: In type 1 and type 2 diabetes, randomized controlled trials of intensive versus standard glycemic control have not shown a significant reduction in CVD outcomes during the randomized portion of the trials. However, long-term follow-up of the DCCT and UKPDS cohorts suggests that treatment to A1C targets below or around 7% in the years soon after the diagnosis of diabetes is associated with long-term reduction in risk of macrovascular disease. Until more evidence becomes available, the general goal of <7% appears reasonable. ADA, B-level recommendation; ACC/AHA, class IIb recommendation (level of evidence A). For some patients, individualized glycemic targets other than the above general goal may be appropriate: Subgroup analyses of clinical trials such as the DCCT and UKPDS and the microvascular evidence from the ADVANCE trial suggest a small but incremental benefit in microvascular outcomes with A1C values closer to normal. Therefore, for selected individual patients, providers might reasonably suggest even lower A1C goals than the general goal of <7% if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Such patients might include those with short duration of diabetes, long life expectancy, and no significant cardiovascular disease. ADA, B-level recommendation; ACC/AHA, class IIa recommendation (level of evidence C). Conversely, less stringent A1C goals than the general goal of <7% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, or extensive comorbid conditions or those with long-standing diabetes in whom the general goal is difficult to attain despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin. ADA, C-level recommendation; ACC/AHA, class IIa recommendation (level of evidence C). For primary and secondary CVD risk reduction in patients with diabetes, providers should continue to follow the evidence-based recommendations for blood pressure treatment, including lipid-lowering with statins, aspirin prophylaxis, smoking cessation, and healthy lifestyle behaviors delineated in the ADA Standards of Medical Care in Diabetes (6) and the AHA/ADA guidelines for primary CVD prevention (15).
