In two trials, tight glycemic control had no significant effect on macrovascular events.
Contrary to popular belief, evidence that intensive glucose-lowering therapy improves macrovascular outcomes in patients with type 2 diabetes is limited. In two new randomized trials, researchers address this issue.
The NIH-sponsored ACCORD study involved 10,251 type 2 diabetic patients (mean age, 62; median glycosylated hemoglobin [HbA1c], 8.1%) with known cardiovascular disease or at least two additional risk factors. Patients received either intensive therapy (target HbA1c, 6%, with antidiabetic regimens individualized by clinicians) or standard therapy (target HbA1c, 7%–7.9%). Although glycemic control was significantly better with intensive treatment than with standard treatment throughout the trial (median HbA1c, 6.4% vs. 7.5%), the trial was stopped after an average follow-up of 3.5 years, because mortality was higher in the intensive-treatment group than in the standard-treatment group (5% vs. 4%; P=0.04). Moreover, the groups did not differ significantly in the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (6.9% vs. 7.2%). Severe hypoglycemia and weight gain were more common in the intensive treatment group, but the factors mediating the higher mortality with intensive treatment were unclear.
The second study — the ADVANCE trial — involved 11,140 patients (mean age, 66; median HbA1c, 7.2%). The intensively treated group received the sulfonylurea gliclazide as initial therapy (with other drugs added as required to reach target HbA1c of 6.5%), and the standard-treatment group received any drugs except gliclazide (with no specified target HbA1c). Although HbA1c averaged 6.5% with intensive treatment and 7.3% with standard treatment during 5 years of follow-up, no significant difference was noted between groups for the primary endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke (10.0% vs. 10.6%) or for all-cause mortality. The microvascular outcome of new or worsening nephropathy occurred significantly less often in the intensive-treatment group (4.1% vs. 5.2%), but severe hypoglycemia was more common with intensive treatment. This study was supported by the maker of gliclazide.
Yet again, presumably favorable modification of a surrogate endpoint — in this case, HbA1c — did not necessarily improve clinical outcomes in high-risk populations. Although why intensive treatment was associated with increased mortality in ACCORD but not in ADVANCE is unclear, the trials are consistent in showing no significant effect of tight glycemic control on macrovascular events. Clinicians should aim for reasonable glycemic control in older diabetic patients, but aggressive attempts to normalize HbA1c are not routinely warranted in this patient population.
Allan S. Brett, MD
Published in Journal Watch General Medicine June 6, 2008
- Patel A et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008 Jun 6; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa0802987)
- Gerstein HC et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008 Jun 6; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa0802743)