Trials examining glycemic targets

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The most hotly debated clinical questions in diabetes mellitus are whether glycemic control is associated with a reduction in CVD outcomes and how low a glycemic target should be pursued. Because the risk for severe hypoglycemia increases as lower targets are achieved, there is a floor below which benefits will be counterbalanced by risk. Guidelines suggest that hemoglobin A1c (HbAlc) targets of less than 7% [3], 6.5% [4], or 6.1% [5] are appropriate. These goals have been imputed by examining epidemiologic studies because there are no CVD outcomes studies in diabetes mellitus that have provided clear-cut, statistically significant reductions in endpoints. Indeed, no reported interventional outcome study has yet achieved the above recommended A1c targets. The clinical trial that comes closest to meeting such criteria is the United Kingdom Prospective Diabetes Study (UKPDS) [6], which suggests that the method of glucose lowering may be more important than the target or the average level of glycemia achieved [7]. Three current clinical trials are testing directly the hypothesis that glucose lowering in the setting of type 2 diabetes mellitus is associated with a reduction in CVD events (Table 1).


In the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), 11,140 patients who have type 2 diabetes mellitus were recruited in 200 centers in Australia, Asia, Europe, and North America. The eligibility criteria are broad: diagnosis of type 2 diabetes mellitus after 30 years of age, age 55 or more years, and high risk for CVD. Patients are randomized in a 2 x 2 factorial design to an open-label, modified-release (MR) sulfonylurea (gliclazide MR)-based intensive treatment with a goal of achieving a HbA1c level of 6.5% or less versus standard care for glycemia as well as a blood pressure intervention (see later discussion). There are two primary endpoints: (1) the composite of stroke, MI, and CV death, and (2) the composite of new or worsening nephrop-athy or microvascular eye disease. The scheduled postrandomization follow-up is 4.5 years. The study is designed to provide 90% power to detect

Table 1

Studies of glycemic control and its relationship to cardiovascular disease outcomes

Table 1

Studies of glycemic control and its relationship to cardiovascular disease outcomes

No. of


A1c target, %


Study [Ref.]









< 6.5

~7.5 (usual care)



VADT [11]



< 6.0





(average 5.6)

< 6.0

7.0-7.9 (expected mean 7.5)





< 95 mg/dL (glargine)

< 7 A1c (standard care with no insulin)


a 16% reduction in the relative risk of each of the primary endpoints for each of the randomized comparisons. More design details are published [8,9] and available on the website for the coordinating center, the George Institute for International Health in Sydney, Australia. In particular, 11,140 patients have been randomized and final results are expected in 2006, with an expected difference in HbA1c levels between randomized arms of 1%. Discussion on the website suggests that the difference between arms remains a challenge for the study [10].


The VADT (Veterans Affairs Diabetes Trial) started in December of 2000 with the goal of enrolling 1700 men and women 41 years of age or older with HbA1c level of 7.5% or higher despite therapy with oral agents or insulin. Volunteers are randomized to an intensive or standard treatment program and followed for 5 to 7 years formajor CV events (MI, stroke, new or worsening congestive heart failure [CHF], amputation for ischemic diabetic gangrene, invasive intervention for coronary or peripheral arterial disease, and CV death). The study is designed to have 86% power to detect a 21% relative reduction in major CV events. In the intensive arm, the goal is to achieve an HbA1c level of 6% or less by sequential addition and titration of metformin, rosiglitazone, or evening intermediate NPH insulin or long-acting insulin glargine to achieve near-normal fasting glucose levels, and subsequent morning or multiple daily injections of short-acting insulins or other therapies as needed (eg, glimepiride and a-glucosidase inhibitors). In the standard arm, the goal is to avoid deterioration in HbA1c, keeping levels at 8% to 9%. The treatment algorithm for the standard group is less rigid and generally uses submaximal doses of oral agents. The investigators expect a difference between arms of 1.5% to 2% in HbA1c level. All patients receive an identical program of individualized diabetes mellitus education, medical nutrition therapy, blood pressure management, lipid management, aspirin therapy, and smoking cessation counseling per American Diabetes Association guidelines. Further details are available in a published methods paper [11].


The ACCORD trial (Action to Control Cardiovascular Risk in Diabetes) examines three independent medical treatment strategies for patients who have type 2 diabetes mellitus. At approximately 70 centers in the United States and Canada, 10,000 patients who have type 2 diabetes mellitus will be randomized in a double 2 x 2 design. All participants will be in the overarching trial that examines glycemic targets. Two subtrials will examine lipid and blood pressure hypotheses (see later discussion). The clinical question tested by the glycemia trial is: ''in middle-aged or older people with type 2 diabetes who are at high risk for having a CVD event because of existing clinical or subclinical CVD or CVD risk factors, does a therapeutic strategy that targets a HbA1c level of < 6% reduce the rate of CVD events more than a strategy that targets a HbA1c level of 7% to 7.9% (with the expectation of achieving a median level of 7.5%)'' [12]. Participants will be treated for 4 to 8 years (mean approximately 5.6 years) with main study results to be reported in 2010. The primary outcome measure of the trial is time to the first occurrence of a major CVD event (MI, stroke, or CV death), with the study designed to have 89% power to detect a 15% treatment effect of intensive glycemic control compared with standard glycemic control.

These three trials should answer definitively the clinical question of whether intensive glucose management will reduce the risk for CVD. Each seeks to achieve glycemic targets below levels reported in large clinical trials, and should inform the discussion about the appropriate targets for glycemic control and the magnitude of the risk of hypoglycemia involved. They also will examine effects on microvascular complications, quality of life, and cost-effectiveness. Because each uses different strategies to achieve different target levels of glycemic control in different populations, they will provide a rich set ofdata to drive future clinical recommendations. Although it is assumed widely that the hypotheses they seek to test are correct, there is substantial doubt as to the outcomes of these studies. Positive results will put tremendous pressure on health care systems to achieve even more stringent levels of control. Negative results will suggest the need to achieve HbA1c levels of approximately 7% to prevent microvascular complications, and that the attention vis-a-vis CV risk management should be on blood pressure, lipid, and thrombotic risk in diabetes mellitus.

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