Intensive glycemic control has no effect on cardiovascular disease in type 2 diabetes

The benefits of intensive glycemic control appear to be confined to microvascular disease, with 3 randomized controlled clinical trials failing to demonstrate a macrovascular benefit with intensive glycemic control in patients with type 2 diabetes. One of the studies, the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), found a 21% reduction in nephropathy with intensive control compared with standard control. Furthermore, one of the other study trials, the VA Diabetes Trial, found hypoglycemia to be a byproduct of intensive control, and this was a major

predictor of cardiovascular events.

ADVANCE was an international study that included 11,140 high-risk type 2 diabetes patients who were randomized to a target hemoglobin (Hb) A1c level of 6.5% or lower (intensive control) or to standard A1c targets. Intensive control in ADVANCE involved a treatment strategy that started with a sulfonylurea and the addition of other drugs (oral agents, long-acting insulin, and multiple insulin injections, if needed) at the treating physician’s discretion to reach the target A1c, although a treatment protocol was suggested. The

intensive strategy also included more frequent visits to the clinic compared with the standard control arm, more frequent monitoring of blood glucose and HbA_1c levels, and an emphasis on lifestyle management.

The achieved average A1c levels were 6.5% in the intensive arm and 7.3% in the standard arm. The incidence of combined major macrovascular and microvascular events was reduced by 10% (P =.01) in the subjects randomized to intensive blood glucose lowering.

Intensive glucose control was associated with a 14% reduction (P =.01) in the risk of microvascular events

compared with standard control, driven by a 21% reduction (P =.006) in the risk of the development or progression of kidney disease in the intensive arm. The intensive intervention had no effect on the incidence of retinopathy.

The incidence of a composite of death and macrovascular complications, a co-primary outcome, was not significantly affected by intensive glucose control: 10.0% in the intensively treated group and 10.6% in the standard treatment arm achieved this outcome (P =.32).

“The study makes it clear for clinicians and their patients the kind of goals that we should be aiming for,

because we can conclude that getting them down to the kind of HbA_1c levels, less than 7% or even approaching 6.5%, can benefit patients from diabetic kidney disease, and essentially protect 1 in 5 over a few years from developing this very bad complication…a feared complication indeed,” said ADVANCE

investigator Stephen MacMahon, DSc, PhD, MPH, professor of cardiovascular medicine and epidemiology, University of Sydney, Australia.

No evidence of an increased risk of death was observed among ADVANCE patients randomized to intensive blood glucose control, unlike in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, the final results of which were presented here as well. ACCORD was sponsored by the National Heart, Lung, and Blood Institute, and terminated prematurely when an interim safety review identified an increase in death in the intensively treated group (HbA_1c goal <6%) compared with the standard glycemic control group (HbA_1c goal of 7.0%—7.9%).

ACCORD included 10,251 adults with type 2 diabetes who were considered at high risk because of a previous myocardial infarction or stroke (35%), indications of subclinical cardiovascular disease, or the presence of major cardiovascular risk factors. The achieved HbA_1c levels in the two treatment strategies were 6.4% in those randomized to the intensive strategy and 7.5% in those randomized to standard

glycemic control.

During 3.5 years of follow-up (planned follow-up was 5 years), significantly more patients in the intensively

treated group died compared with the standard control group (5.1% vs. 4.0%; P =.04). The primary outcome of the trial, which was the first occurrence of a major fatal or nonfatal cardiovascular event, was achieved by 10% fewer patients assigned to the intensive strategy, but this difference failed to achieve statistical

significance (P =.16). Intensive therapy was associated with a 35% increase (P =.02) in cardiovascular death and a 24% reduction (P =.004) in nonfatal MI. There was no difference between the two strategies in the occurrence of nonfatal stroke or heart failure.

Hertzel Gerstein, MD, MSc, an ACCORD investigator and professor of medicine at McMaster University, Ontario, Canada, attributes the increase in mortality in the intensively treated group to the strategy itself and not the medications, since the same types of drugs were used to achieve glycemic control for each strategy. “ We learned something about the risks, at least over a 3.5-year period of time, of rapidly lowering high A1c levels targeting perfectly normal levels…it doesn’t tell us what would happen if we took a group of better controlled patients, somewhat more like the ADVANCE participants,” said Dr Gerstein.

The VA Diabetes Trial enrolled 1791 veterans who failed to achieve control on at least 1 oral antidiabetes drug, insulin, or a combination of these. On average, participants had diabetes for 11 years. The average A1c on entry was 9.5%. Subjects were randomized to intensive or standard control; the achieved A1c levels were 6.9% and 8.4% at 6 months in the 2 groups, respectively.

Because of the high A1c levels at baseline and the high rate of previous cardiovascular events among the patients (40% had a previous event), the population studied in the VA Diabetes Trial was a higher-risk population than those enrolled in ADVANCE and ACCORD, said William C. Duckworth, cochair of the trial, and director of diabetes research, Carl T. Hayden VA Medical Center, Phoenix. There were significantly

fewer cardiovascular events in each group than predicted, probably because of excellent control of cardiovascular risk factors, he said.

There was no significant difference between groups in the rate of cardiovascular events (P =.12) or the number of deaths. An episode of severe recent (within the past 3 months) hypoglycemia more than doubled the risk of cardiovascular death and more than tripled the risk of total death. A longer duration of diabetes also predicted a worse outcome. “The benefit [of intensive treatment] goes away if you to wait to treat,” said Dr Duckworth. “Intensive therapy may be harmful in this situation. But if you treat early enough, you might get benefits on both microvascular and macrovascular events. The simple answer is to start treating early after diagnosis, no matter how old the patient. There should also be a large emphasis on reducing severe

hypoglycemia.”