Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation - ADVANCE

Jun 06, 2008
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Major: Servier (manufacturer of gliclazide and fixed dose combination of perindopril and indapamide); Other: National Health and Medical Research Council of Australia
Date Presented:
01/01/2008
Date Published:
01/01/2008
Date Updated:
06/06/2008
Original Posted Date:
06/06/2008
References

Description:

Patients with type 2 diabetes were randomly assigned to undergo either standard glucose control or intensive glucose control with gliclazide and other agents to achieve a glycated hemoglobin (HbA1c) value of ≤6.5%.

Hypothesis:

Intensive glucose control, with an HbA1c of ≤6.5% is associated with a decreased incidence of macrovascular and microvascular complications in patients with type 2 diabetes, compared with standard control.

Study Design

  • Factorial
  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patients Screened: 12,877
Patients Enrolled: 11,140
Mean Follow Up: 5 years
Mean Patient Age: 65.8 years
Female: 43

Patient Populations:

• Age ≥30 years at time of diagnosis of diabetes
• Age ≥55 years
• History of major macro- or microvascular disease, or one other risk factor for vascular disease

Exclusions:

• Definite indication or contraindication to any of the study treatments
• Definite indication for long-term insulin therapy at the time of enrollment

Primary Endpoints:

The primary endpoint was a composite of:
• Major macrovascular complications: nonfatal stroke, nonfatal acute coronary syndrome, and death from cardiac causes
• Major microvascular complications: new or worsening nephropathy or microvascular eye disease

Secondary Endpoints:

• Death from any cause
• Death from cardiac causes
• Major coronary events (death due to coronary heart disease/sudden cardiac death, or nonfatal MI)
• Total coronary events (major coronary events, silent MI, coronary revascularization, or hospital admission for angina
• Major cerebrovascular events (death due to cerebrovascular disease or nonfatal stroke)
• Total cerebrovascular events (major cerebrovascular events, transient ischemic attack, subarachnoid hemorrhage
• Heart failure
• Peripheral vascular events
• All cardiovascular events
• New or worsening nephropathy
• New or worsening retinopathy
• New or worsening neuropathy
• Development of microalbuminuria
• Visual deterioration
• Decline in cognitive function
• Dementia
• Hospitalization for >24 hours
• Hypoglycemic events

Drug/Procedures Used:

Patients who were randomly assigned to undergo intensive glucose control were given gliclazide modified release 30-120 mg daily, and were required to discontinue any other sulfonylurea. Once gliclazide was maximized, agents such as metformin, thiazolidinediones, acarbose, and/or insulin were added on. Patients in the standard glucose control group received usual level of care. If they were on gliclazide prior to enrollment, it was stopped, and another sulfonylurea was introduced.

Concomitant Medications:

At the end of the trial: Metformin (68.1%), thiazolidinedione (13.4%), insulin (32.3%), aspirin (54%), statins (45%), and any blood pressure lowering agent (88.6%)

Principal Findings:

ADVANCE was a 2 x 2 factorial study, in which patients were randomized to either intensive glucose control or standard glucose therapy, and fixed-dose combination of perindopril and indapamide, or placebo. After a 6-week run-in phase during which patients continued their usual glucose control, patients who tolerated and complied with the blood pressure regimen were randomized to either intensive glucose control, with an HbA1c of ≤6.5%, or a strategy of standard glucose control. A total of 11,140 patients were randomized, 5,571 to the intensive control arm, and 5,569 to the standard control arm. Baseline characteristics were fairly similar between the two groups. The baseline HbA1c was 7.5%; the mean duration of diabetes was about 8 years. About 32.2% of patients had a history of macrovascular disease, and about 10.4% of patients had a history of microvascular disease.

At the end of 5 years, the mean HbA1c was 6.5% in the intensive control arm versus 7.3% in the standard therapy arm (p

There was an excess risk of hospitalization from any cause in patients in the intensive control arm (HR 1.07, 95% CI 1.01-1.13, p = 0.03), and a higher incidence of severe hypoglycemia (HR 1.86, 95% CI 1.42-2.40, p

Interpretation:

ADVANCE is the largest ever study on diabetes treatments, and demonstrates that gradually implemented intensive glucose control, with a goal to achieve an HbA1c of ≤6.5%, is associated with a significant reduction in some microvascular complications of diabetes, mainly diabetic nephropathy, but not macrovascular complications, at the end of 5 years of follow-up. Intensive glucose control is, however, associated with a higher incidence of hospitalizations and severe hypoglycemia. Patients in the intensive control arm also were followed up an average of 6 times a year versus 1.5 times in the standard control arm. In real-world practice, such intensive levels of follow-up are likely to be difficult to achieve, with a possible higher incidence of hypoglycemic events.

The recently presented ACCORD trial demonstrated a higher mortality in diabetic patients randomized to intensive glucose control, when the HbA1c goal was ≤6.0%. The contrasting results between ACCORD and ADVANCE suggest that the optimal HbA1c goal for diabetic patients may lie between 6.0% and 6.5%, especially with a view to reducing microvascular complications of diabetes, while minimizing the incidence of hypoglycemia.

There was also a difference between the two trials in terms of approaches to lowering HbA1c, as well as the pace and intensity of HbA1c lowering. The results of the recent PERISCOPE trial also suggest that the strategy to reduce HbA1c in diabetic patients may be as important as actual reductions in HbA1c. Further studies addressing these issues specifically are necessary.

References:

The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72.

Keywords: Perindopril, Insulin, Follow-Up Studies, Diabetes Mellitus, Type 2, Vascular Diseases, Risk Factors, Blood Pressure, Diabetic Nephropathies, Hypoglycemia, Glucose, Glycated Hemoglobin A, Sulfonylurea Compounds, Metformin, Gliclazide, Hypoglycemic Agents, Acarbose, Indapamide, Hospitalization, Thiazolidinediones


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