Studies Find Minimal Cardiovascular Benefit and Increased Mortality with Intensive Glucose Management for People with Type 2 Diabetes

By Liz Highleyman

Abnormal blood glucose metabolism - including insulin resistance and frank type 2 diabetes - are common in people with HIV, though it is not yet clear whether this is primarily related to chronic HIV infection itself, antiretroviral therapy, normal aging as HIV positive people live longer, or other unknown factors.

Blood glucose abnormalities are a concern since they have been linked to increased risk of cardiovascular disease in large studies of the general population. Much remains to be learned, however, about how best to manage insulin resistance and diabetes.

Coinciding with the American Diabetes Association's 68th Scientific Sessions, articles describing 2 large trials of diabetes management were published June 6, 2008 in the online edition of the New England Journal of Medicine (in print June 12).

ACCORD

The first study, called ACCORD (Action to Control Cardiovascular Risk in Diabetes), investigated whether intensive therapy to reduce glycated hemoglobin would reduce the incidence of cardiovascular events in patients with type 2 diabetes who had either pre-existing cardiovascular disease or additional risk factors.

Glycated hemoglobin is a measure used to assess blood glucose concentrations over time, and is considered more reliable than plasma glucose levels measured at specific time points. The normal range for glycated hemoglobin is 4% to 6%, with higher levels indicating impaired glucose metabolism.

In this randomized North American study, 10,251 participants (62% men; mean age 62 years; 35% with a previous cardiovascular event) with a median baseline glycated hemoglobin level of 8.1% were assigned to receive either intensive therapy with multiple oral drugs and insulin aimed at bringing glycated hemoglobin below 6.0%, or else standard therapy with a target level of 7.0% to 7.9%.

The primary outcome was a composite endpoint of nonfatal myocardial infarction (heart attack), nonfatal stroke, or death due to cardiovascular causes.

Results

• At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive therapy and standard therapy groups, respectively.

• During follow-up, the primary outcome occurred in 352 patients in the intensive therapy group, compared with 371 in the standard therapy group (hazard ratio [HR] 0.90; P = 0.16).

• 257 patients in the intensive therapy group died, compared with 203 in the standard therapy group (HR 1.22; P = 0.04).

• Excess deaths in the intensive treatment group were mainly due to cardiovascular causes (myocardial infarction, stroke, congestive heart failure, cardiac arrhythmia, or invasive interventions) (135 vs 94 deaths; HR 1.35).

• Hypoglycemia (low blood sugar) requiring medical assistance (16.2% vs 5.1%) and weight gain of more than 10 kg (27.8% vs 14.1%) were significantly more common in the intensive therapy group (both P < 0.001).

• The higher mortality in the intensive therapy group led to premature discontinuation of the intensive therapy arm of the study after a mean 3.5 years of follow-up.

"As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events," the study investigators concluded. "These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes."

The researchers noted that the elevated mortality in the intensive control group could not be attributed to use of rosiglitazone (Avandia) - which has previously been linked to adverse cardiovascular events -- or hypoglycemia. Only certain types of insulin were associated with significantly higher mortality. They suggested that the strategy of rapidly driving down glucose levels was itself the likely reason for the increased mortality observed in the intensive therapy group.

ADVANCE

The second study, called ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation), also studied the impact of intensive glucose control on cardiovascular outcomes in people with type 2 diabetes.

In this international trial, 11,140 participants with type 2 diabetes and a mean baseline glycated hemoglobin level of 7.5% were randomly assigned to receive either standard glucose control therapy or intensive glucose control using a modified release formulation of the anti-diabetic drug gliclazide (Diamicron; not available in the U.S.) plus other drugs as needed to achieve a glycated hemoglobin level of 6.5% or lower.

The primary endpoints were composites of the same major "macrovascular" events used in the ACCORD trial (nonfatal myocardial infarction, nonfatal stroke, and death due to cardiovascular causes) and 2 major "microvascular" events, new or worsening nephropathy (kidney damage) and retinopathy (damage to the retina of the eye).

Results

• After a median follow-up period of 5 years, the mean glycated hemoglobin level was lower in the intensive control group compared with the standard therapy group (6.5% vs 7.3%, respectively).

• Patients in the intensive control group used more oral hypoglycemic drugs including metformin (Glucophage) and thiazolidinediones, as well as insulin.

• Intensive glucose control was associated with a lower incidence of combined major macrovascular and microvascular events (18.1% vs 20.0%, respectively; HR 0.90; P = 0.01).

• The intensive control group also had a lower risk of major microvascular events considered alone (9.4% vs 10.9%; HR 0.86; P = 0.01).

• This was primarily attributable to a reduction in the incidence of nephropathy (4.1% vs 5.2%; HR 0.79; P = 0.006), with no significant difference in the rate of retinopathy (P = 0.50).

• Intensive glucose control had no significant effect on major macrovascular events considered alone (HR 0.94; P = 0.32), death due to cardiovascular causes (HR 0.88; P = 0.12), or death from any cause (HR 0.93; P = 0.28).

• Severe hypoglycemia (although uncommon overall) was more common in the intensive control group (2.7% vs 1.5%; HR 1.86; P < 0.001).

The ADVANCE researchers concluded that, "A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5%, yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy."

Editorials

Taken together, the ACCORD and ADVANCE trials indicate that intensive therapy to reduce blood glucose below the standard target has little benefit with regard to major cardiovascular outcomes, and may in fact be harmful.

In one accompanying editorial, William Cefalu, MD, of Louisiana State University in Baton Rouge wrote that the 6% glycated hemoglobin target for the intensive control group may have been too aggressive, suggesting that "7% may be appropriate in this high-risk population."

The American Diabetes Association continues to recommend a glycated hemoglobin target of below 7%.

In another commentary, Harlan Krumholz, MD, of Yale University and Thomas Lee, MD, of Partners Healthcare System in Boston suggested that the 2 studies may have erred in focusing on glycated hemoglobin levels rather than clinical outcomes.

Since the ACCORD and ADVANCE trials included only high-risk patients, it is unclear how applicable the findings might be to a lower-risk population.

In yet another editorial, Robert Dluhy, MD, and Graham McMahon, MD, of Brigham and Women's Hospital concluded that, "We may best serve our patients with type 2 diabetes by implementing programs to help more of them reach the currently recommended goals."

6/20/08

References

HC Gerstein, ME Miller, RP Byington, and others (Action to Control Cardiovascular Risk in Diabetes Study Group). Effects of Intensive Glucose Lowering in Type 2 Diabetes. New England Journal of Medicine 358(24): 2545-2559. June 12, 2008.

A Patel, S MacMahon, J Chalmers, and others (ADVANCE Collaborative Group). Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine 358(24): 2560-2572. June 12, 2008.

RG Dluhy and GT McMahon. Intensive Glycemic Control in the ACCORD and ADVANCE Trials. New England Journal of Medicine 358(24): 2630-2633. June 12, 2008.

WT Cefalu. Glycemic targets and cardiovascular disease. New England Journal of Medicine 358(24): 2633-2635. June 12, 2008.

HM Krumholz and TH Lee. Redefining quality--implications of recent clinical trials. New England Journal of Medicine 358(24): 2537-2539. June 12, 2008.