Diabetes Self-Management Blog

Three large studies presented at the American Diabetes Association’s (ADA) Scientific Sessions meeting in the last week have shed some light on the question of whether tight control of blood glucose levels helps prevent cardiovascular disease (CVD) in people with Type 2 diabetes. None of the trials found that tight control was associated with a lower risk of CVD, and one found an increased risk of death among the participants practicing more intensive control.

The results of the ADVANCE and ACCORD trials were published online in The New England Journal of Medicine on June 6. Analysis of data from the third trial, the VA Diabetes Trial (VADT), is ongoing and its findings will be published at a later date.

While the three studies had similar goals, their designs, methods, participants, and lengths of follow-up all varied, making them difficult to compare directly. Over my next few blog entries, I’ll take a closer look at the results of all three studies and what effect their findings may have on diabetes control recommendations.

The ADVANCE Study
The “Action in Diabetes and Vascular Disease” (ADVANCE) study enrolled 11,140 people in 20 countries and has been billed as “the world’s largest diabetes trial.” It had two branches, a blood-pressure-lowering arm and a blood-glucose-lowering arm. (The results of the blood-pressure arm, which showed that treatment with blood-pressure-lowering drugs lowered cardiovascular risks significantly, were published in the journal The Lancet in September 2007.) The primary aims of the blood-glucose-lowering arm were to see whether lowering HbA1c levels to 6.5% or lower in people with Type 2 diabetes would reduce their risk of “macrovascular” complications (heart attack, stroke, and cardiovascular death) and two “microvascular” complications, diabetic nephropathy (kidney disease) and retinopathy (eye disease). Secondary outcomes that were measured included diabetic neuropathy (nerve disease), cognitive function, dementia, and death from all causes.

Participants had an average age of 66, body-mass index (BMI) of 28, and HbA1c of 7.5%, and had had diabetes for an average of eight years at the beginning of the trial. They were all considered to be at high cardiovascular risk; about one-third had already had a “cardiovascular event” such as a stroke or heart attack, and the rest had at least one cardiovascular risk factor in addition to diabetes, such as protein in the urine (a sign of kidney problems), proliferative diabetic retinopathy, high total cholesterol, low HDL (”good”) cholesterol, or smoking.

The participants were randomly assigned to be in the intensive glucose control group or the standard group and followed for an average of five years. People in the intensive group were treated with the sulfonylurea drug gliclazide MR (brand name Diamicron, which is not available in the U.S.) as well as up to three other oral diabetes drugs and insulin as needed; they achieved an average HbA1c of 6.5% by the end of the study. The standard group members did not receive gliclazide, but were otherwise treated with their physician’s choice of medicines; they achieved an average HbA1c of 7.3% by the end of the study. Over the course of the trial, the average difference in HbA1c between the two groups was 0.7%.

Results
At the end of the study, the researchers found the following:

  • No significant difference in major macrovascular events—heart attack, stroke, and cardiovascular death—or death from all causes between the two groups
  • A 21% reduced risk of diabetic kidney disease in the intensive control group
  • No significant difference in risk of diabetic eye disease between the two groups
  • No significant difference in rates of heart failure, neuropathy, dementia, or cognitive function between the two groups
  • Significantly more hypoglycemia (low blood glucose) and severe hypoglycemic events in the intensive control group
  • No change in weight in the intensive control group, and a slight reduction in weight in the standard group

While intensive control showed a clear benefit for helping to prevent kidney disease, it did not show the reduction in cardiovascular risk that the researchers had hoped for based on previous studies, even when data on different subgroups within the study were analyzed. Why is this?

The researchers offered several possible explanations for their findings. For one thing, they began to see a trend toward lower rates of cardiovascular events in the intensive control group toward the end of the study period; while this trend was not statistically significant, they believe that it may have become so if the study had gone on longer. In other words, it may take more than five years for intensive blood glucose control to result in measurable cardiovascular benefits. The researchers stated that such potential benefits may be related to the reduction in kidney disease that was found with intensive control, since diabetic nephropathy “is a powerful predictor of death from cardiovascular disease.”

The researchers also noted that fewer benefits may have been seen in the intensive group in this study because the standard group was in such good control. (For comparison, in the landmark United Kingdom Prospective Diabetes Study [UKPDS], which found reductions in microvascular complications associated with lower blood glucose levels in people with Type 2 diabetes, the intensive control arm achieved an HbA1c of 7% while the standard arm’s HbA1c was 7.9%.)

Finally, the results of a substudy of 2,000 ADVANCE participants who received more sensitive retinal exams will be reported later this year and may shed more light on whether intensive control in this study had an effect on rates of eye disease.

The Take-Home Message
The ADVANCE trial researchers suggested that people with longstanding Type 2 diabetes and high cardiovascular risk continue to focus on controlling their blood pressure and blood lipid (cholesterol and triglycerides) levels to ward off CVD. However attempting to achieve very tight blood glucose control, while safe, may not provide much added benefit in this area. Tight control does, however, appear to provide benefit in reducing kidney disease.

For our previous coverage of the ADVANCE trial, please see the blog entry “ADVANCE Study Contradicts ACCORD Findings.” And stay tuned for coverage of the ACCORD trial and VADT results over the next few weeks.

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Comments
  1. Good job summarizing this study, Tara!

    I admit I haven’t read the study yet. Ideally, scientists like to see only one variable between the study group and the control group. That way you avoid “confounding variables.”

    In the study at hand, investigators studied two groups but introduced two variables into one group: “tight control” AND gliclazide.

    So I suppose it’s possible the improvement in renal disease seen in the “tight control” group was related to gliclazide rather than tight control. Since it’s not available in the U.S., I’m not familiar with it. I would not assume that all sulfonylureas are equal.

    I would hope that previous studies showed that gliclazide conferred no particular benefit to the kidneys compared with other hypoglycemic drugs. Then the researchers could reasonably use gliclazide as they did.

    But why not just study “tight control” versus “usual care”? Then let both groups use gliclazide.

    I better read the original full report!

    -Steve

    Posted by Steve Parker, M.D. |
  2. You can read the entire study, as I did, at NEJM:
    http://content.nejm.org/cgi/content/full/358/24/2560

    The authors never explain why they chose gliclazide (a sulfonylurea) as a study drug in the intensive control group. The “usual care” group was not allowed to use any other sulfonylurea. They never consider that gliclizide in particular may be protective of the kidneys.

    UpToDate.com indicates that there is nothing special about gliclizide that would protect the kidneys.

    The investigators lumped people together from 20 different countries. Are Asian diabetics identical to North American?

    Overall, I’m not favorably impressed with the design of ADVANCE. And the report is not very well written.

    -Steve

    Posted by Steve Parker, M.D. |
  3. Hi Steve,

    As I mentioned in my first post about ADVANCE,
    “ADVANCE Study Contradicts ACCORD Findings,” Servier, the company that manufactures gliclazide, helped fund this study. The researchers state that the study was “investigator-initiated and conducted,” though, and that “Gliclazide MR was included as a standard component of the intensive control regimen in ADVANCE because of its known effectiveness and safety in lowering blood glucose with the convenience of once-daily administration (as a result of the modified-release formulation).”

    They also say that the global design of the study was meant to reflect the global problem of Type 2 diabetes.

    You can read more at .

    Posted by Tara Dairman, Web Editor |

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