Dr. Ford is a clinical pharmacy specialist at the University of North Carolina Hospitals and an assistant professor at the University of North Carolina Department of Family Medicine.
Patients with diabetes have a 2- to 4-fold higher risk of stroke and death from heart disease compared with people without diabetes. Hyperglycemia also causes damage to the microvasculature, leading to blindness, kidney disease requiring dialysis, neuropathy, and amputations. These risks can be reduced with a combination of exercise, healthy eating habits, and medications.
Another important factor in improving diabetes care is education to empower patients with information to better manage the disease themselves. Pharmacists are in a unique position to educate patients on medicines for glucose control and those used to manage or prevent complications of diabetes.
Improving glycemic control is known to reduce the risk of microvascular complications of diabetes, but previous studies have failed to demonstrate a reduction in cardiovascular disease (CVD) with improved glycemic control. The United Kingdom Prospective Diabetes Study (UKPDS),1 published in 1998, showed a 25% reduction in microvascular complications—but no difference in macrovascular disease—in patients with type 2 diabetes randomized to intensive glycemic control with insulin and sulfonylureas, compared with standard control. Patients in the intensive control group achieved a mean A1C of 7%, compared with 7.9% in the standard control group. Current American Diabetes Association (ADA) guidelines2 recommend targeting a goal A1C of <7% in the general population of patients with type 2 diabetes, although most other organizations recommend lower A1C targets.
Two recently reported trials—ACCORD3 and ADVANCE4—were designed to test the effects of more intensive glycemic control on vascular outcomes in type 2 diabetes patients. The ACCORD trial received extensive media attention when a press conference was held in March announcing an increase in mortality in the intensive control group. The ADVANCE study, which did not demonstrate an increase in mortality in the intensive control group, was published simultaneously with ACCORD in June 2008.
The ACCORD trial3 is a prospective randomized study of 10,251 patients to determine whether intensive glycemic control (goal A1C of <6%) would reduce the rates of cardiovascular events compared with standard therapy (goal A1C of 7%-7.9%) in patients with type 2 diabetes and CVD or at high risk for vascular events. After a mean of 3.5 years of follow-up, the rates of all-cause mortality were 5% in the intensive glycemic control group and 4% in the standard therapy group (hazard ratio, 1.22; P = .04), indicating an increase in 1 death per 100 patients treated with intensive therapy over 3.5 years. An increase in cardiovascular mortality was noted with intensive therapy compared with standard therapy (0.79% annually vs 0.56%; hazard ratio, 1.35; P = .02). Of note, annual rates of nonfatal myocardial infarction were decreased with intensive therapy compared with standard therapy (1.11% vs 1.45%; hazard ratio, 0.76; P = .004).
Median A1C levels at follow-up were 6.4% and 7.5% in the intensive and standard therapy groups, respectively, from a baseline of 8.1%. Rates of hypoglycemia requiring assistance were significantly higher in the intensive control group compared with the standard control group (16.2% vs 5.1%; P <.001). Similarly, weight gain >10 kg was more common with intensive therapy—28% over 3.5 years, versus 14% in the standard group. Despite many analyses, the investigators were unable to determine an explanation for the finding of increased mortality with intensive therapy, including an analysis of the potential contribution of specific drugs such as rosiglitazone. Data on microvascular disease were collected during this study, but have not yet been published.
The ADVANCE trial4 also aimed to determine the effects of intensive glucose control on major vascular events in patients with type 2 diabetes. Similar to the ACCORD study, patients were included only if they had documented macrovasular or microvasular disease or risk factors for vascular disease; >11,000 patients were enrolled. ADVANCE participants had lower A1C levels at baseline and a shorter duration of diabetes and could not be treated with insulin prior to entry. Patients randomized to intensive glucose control were treated with a specific sulfonylurea.gliclazide.plus other medications determined at the discretion of the treating physician to a goal A1C of .6.5%. Patients randomized to standard glucose control were treated to a goal A1C determined by local guidelines.
After a median duration of follow-up of 5 years, the median A1C in the intensive glucose control group was 6.3%, compared with 7.0% in the standard glucose control group, from a baseline of 7.2%. Patients in the intensive control group experienced significantly fewer major microvascular events (mostly a reduction in new or worsening nephropathy) than those in the standard control group (9.4% vs 10.9%; hazard ratio, 0.86; P = .01), but no difference was reported in the incidence of major macrovascular events.
In contrast to findings in the ACCORD trial, investigators found no difference in all-cause mortality between the 2 groups (8.9% in the intensive control group vs 9.6% in the standard control group; hazard ratio, 0.93; P = .28). Severe hypoglycemia (defined as hypoglycemia requiring help from another person) occurred at least once in 2.7% of patients in the intensive control group and in 1.5% of patients in the standard control group (hazard ratio, 1.86; P <.001). No increase in weight in the intensive participants versus standard was reported.
Additionally, results of a 10-year postintervention follow-up of intensive glucose control in the UKPDS were recently published.5 By the end of the first year after study completion, the difference in A1C from the original study (7% vs 7.9% in the intensive control group vs conventional control) had disappeared, and similar A1Cs were maintained through the 10-year postinterventional followup. At 10 years, patients in the intensive control group maintained a lower risk of microvascular disease, and reductions in the risks of diabetes-related death, death from any cause, and myocardial infarction emerged in the group of patients originally allocated to intensive control. These data indicate that the known microvascular benefits of intensive glycemic control persist despite loss of glycemic control, and although improved glycemic control may not have an immediate effect on macrovascular disease, there may be long-term benefits.
Finally, data from another trial designed to test the effects of intensive glycemic control on macrovascular disease, the Veterans Affairs Diabetes Trial (VADT), were presented recently at the ADA Scientific Meeting in June.6 The aim of this trial was to lower A1C levels in the intensive treatment group to as close to normal as possible. Patients in the intensive control arm achieved a mean A1C of 6.9%, compared with 8.4% in the control arm. No statistically significant reduction in cardiovascular events was seen, which is consistent with the results of ACCORD and ADVANCE. Further data will be available when VADT is published.
The data from these recent studies create more questions than answers. Mounting evidence has been reported that improving glycemic control does not substantially decrease the risk of macrovascular disease, except perhaps in individuals with earlier disease and longer follow-up and even then at modest effect.
The ACCORD trial and the VADT suggest that inherent risks may exist with more intensive glycemic control, although these risks were not apparent in the gentler ADVANCE trial. This disparity may be due to differences in the medications and intensity of application to lower A1C, differences in preventive medications, or differences in the populations between the 2 studies.
In light of the increased mortality with lower A1C levels in the ACCORD study, it is likely prudent to follow the ADA recommendations to target an A1C of <7% instead of more intensive glycemic control, until more information is available on the risks and benefits of lowering A1C levels further. When counseling patients, it is important to emphasize the known benefits of glycemic control in reducing microvascular complications of diabetes. Patients should be advised not to stop their diabetes medications without first talking to their doctor or other diabetes provider.
Additionally, as more information is available on the risks and benefits of intensive glycemic control, it is important to remember those interventions that are known to reduce the risk of CVD in patients with diabetes.smoking cessation, aspirin, and treatment of hypertension and dyslipidemia.
Acknowledgment: John Buse, MD, PhD, professor and chief, Division of Endocrinology and Metabolism, Department of Medicine, University of North Carolina, and president, Medicine and Science, American Diabetes Association, for his review, commentary, and expertise in the preparation of this manuscript.