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How low can HbA1c go?
After ACCORD, ADVANCE, and the VA Diabetes Trial, clinicians question intensive glucose control.
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For clinicians who treat patients with type 2 diabetes, tight glycemic control has long been a staple of good disease management. Results from the ACCORD, ADVANCE, and VA Diabetes Trial, all presented at this year’s American Diabetes Association Annual Meeting, however, have shaken up the current thinking about intensive glucose control.
“My ‘religion’ for 30 years has been [that] the tighter the control the better,” said David S. H. Bell, MB, FACE, a professor of medicine at the University of Alabama School of Medicine, Birmingham. “For years we have believed that, based on good data, one can prevent cardiac events by excellent glycemic control, and that the lower the better,” added Bell, a member of the Endocrine Today Editorial Board. In fact, the notion that lowered HbA1c levels could possibly be associated with an increased risk of death goes against his basic beliefs, he said.
In February 2008, the National Heart, Lung, and Blood Institute announced that it would curtail the intensive treatment arm of the North American ACCORD study. According to results presented at ADA in June, of the 10,251 patients enrolled in ACCORD, those assigned to the intensified glucose lowering arm (n=5,128) had a 22% higher relative risk for death compared with patients assigned to the standard glucose control arm — an absolute mortality increase of about 1% during 3.5 years of treatment and follow-up.
“A thorough review of the data shows that the medical treatment strategy of intensively reducing blood sugar below current clinical guidelines causes harm in these especially high-risk patients with type 2 diabetes,” said NHLBI director Elizabeth G. Nabel, MD, in the press release after the ACCORD results were first released. “Though we have stopped this part of the trial, we will continue to care for these participants, who now will receive the less-intensive standard treatment. In addition, we will continue to monitor the health of all participants, seek the underlying causes for this finding, and carry on with other important research within ACCORD.”
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To confound matters further, shortly after the NHLBI publicized these findings, researchers from the international ADVANCE trial announced that their interim data did not reflect a difference in mortality among patients with type 2 diabetes in the trial’s high-intensity and standard treatment groups.
The ADA quickly responded, saying that it “continues to advise most people with diabetes to strive for an HbA1c of <7%, but stresses individualization of treatment goals.”
The ADA’s recommendations of HbA1c <7% has not changed since its annual meeting in June.
Clinicians and their patients have attempted to draw conclusions from these seemingly similar but significantly different trials. Endocrine Today turned to researchers affiliated with the trials, as well as various practicing clinicians, to weigh in on the issue.
Results cause commotion
Researchers launched the ACCORD trial to test the effects of three complementary medical treatment strategies on cardiovascular disease morbidity and mortality in patients with type 2 diabetes. They recruited patients with type 2 diabetes at high risk for CVD or with existing CVD to assess the effects of intensive glycemic control, of treatment to increase HDL and lower triglycerides, and of intensive blood pressure control on major CVD events. Baseline data appeared in The American Journal of Cardiology in 2007.
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Photo by Susan Dambrauskas |
“We were testing whether intensively lowering blood sugar levels to target normal or near-normal levels would prevent CVD events like myocardial infarction, stroke and cardiovascular death, in patients with diabetes. [We enrolled patients] who were at especially high risk for those CVD events because they either already had CVD or had at least two additional risk factors,” explained Denise G. Simons-Morton, MD, PhD, the NHLBI project officer for ACCORD and a member of the ACCORD steering committee. She and her fellow colleagues were targeting an HbA1c of <6% in the intensive-treatment group vs. an HbA1c between 7% and 7.9% in the standard treatment group.
Findings showed that targeting a lower HbA1c level was more likely to lead to a fatal event. The secondary outcome — rate of cardiovascular death due to MI, heart failure and arrhythmia — was 35% higher in the intensive group, according to results presented at ADA. Additionally, hypoglycemia and weight gain more than 10 kg were more common among intensive therapy patients (P<.001).
“When we observed this higher mortality, we undertook a number of analyses of the data to try to explain why it had occurred,” William T. Friedewald, MD, said of the original study results. Friedewald is the ACCORD steering committee chair and clinical professor of medicine and public health at Columbia University in New York. “We looked at several subgroups: Were there people who had experienced prior heart attacks who were at an increased risk [of death]? Were patients with hypoglycemia at an increased risk? Was rosiglitazone use a factor? When we went through these analyses, there was no subgroup that had a particularly higher mortality compared with patients not in that subgroup.”
“In a randomized trial, the only factors you can be sure cause the outcome are those that are different between the groups,” Simons-Morton added.
“All we know is that the intensive group received more intense treatment, increased insulin, and that they had to work harder at lowering their HbA1c levels,” Friedewald continued. “We don’t know if any or all of these factors explain the difference in mortality. Our initial expectation was that as we decreased the HbA1c levels, the mortality would be decreased as well. … After several months of analyzing the data, we really could not find a specific cause of it,” he said, adding that the observed mortality was in fact lower than had been expected for these people out of the general community.
No increased risk
In a prepared statement prior to the ADA annual meeting, researchers with the ADVANCE trial announced that their interim results of 11,140 high-risk patients with type 2 diabetes provided no evidence of an increased risk of death among those patients receiving intensive treatment to lower blood glucose.
“These findings contrast with those reported [recently] by the U.S. NHBLI suggesting that intensive glucose lowering treatment levels had increased the death rate among patients with diabetes recruited to the ACCORD trial,” according to the press release.
Pavel Hamet, MD, professor of medicine, Canada Research Chair of Predictive Genomics at Université de Montréal and Canadian lead investigator and a member of the ADVANCE management committee, explained that the trial was designed to answer two questions in patients with type 2 diabetes: Does intensive treatment to lower blood pressure improve outcome? Does intensive treatment to reduce blood glucose improve outcome?
In September 2007, the ADVANCE Collaborative Group published evidence in The Lancet demonstrating that the blood pressure–lowering treatment had reduced the death rate among patients. In January 2008, the portion of the study designed to assess the effects of the intensive treatment to reduce blood glucose was completed. As in ACCORD, this intensive treatment program was designed to lower blood glucose to levels below those usually recommended by clinical guidelines (ie, <6.5%). The treatment regimen included a sulfonylurea drug, gliclazide (Diamicron MR, Servier), for all patients, as well as a range of other drugs for those not reaching target blood glucose levels.
Most recent results of ADVANCE, presented at ADA, showed that after five years of treatment with an intensive glucose lowering strategy, patients achieved a target HbA1c of <6.5%. Compared with patients who received the standard treatment, those in the intensive arm had an overall lower risk of serious diabetes complications of 10% (HR=0.90; 95% CI, 0.82-0.98), largely driven by a reduction in nephropathy of 21% (HR=0.79; 95% CI, 0.66-0.93).
“We were able to achieve an HbA1c mean level of 6.5% with remarkably few side effects. The study showed no evidence of any increased risk of death when blood glucose was intensively controlled, there was no clear increase in weight and the incidence of hypoglycemic events was remarkably low,” Stephen MacMahon, PhD, a co-principal investigator of ADVANCE, said during a session at ADA.
Experts look for answers
Ever since the ADVANCE researchers announced that their mortality data conflicted with the ACCORD results, clinicians have been forced to wonder: What factors could have possibly accounted for the difference in outcome?
“We will have to analyze all the possibilities,” Hamet said. “We will have to analyze what the patient population looks like.” He started by describing that the ADVANCE researchers enrolled patients in Europe, Asia, Australia and Canada — not the United States. “Canada is the only country that is the same between the ADVANCE and ACCORD trials.” Perhaps characteristics of the U.S. patient population adversely affected outcomes. However, Hamet admitted that relying on such a factor to explain these differences is likely a stretch. “We may have recruited different patients, but they should be very similar. With type 2 diabetes, age is similar among patients and presence of complications is similar, as well.”
Perhaps disparate protocols had an effect. “The treatment protocol in ADVANCE is based on one single hypoglycemic agent, and then anything else can be added to it to achieve good control,” Hamet said. “In ACCORD, it’s similar, but there is a lot more emphasis in the beginning on the intervening therapy. So there are differences in protocol.”
Simons-Morton agreed that there were various differences between the two trials. “In ACCORD, we were testing treatment of any one of several medications available on a formulary to be used by clinicians. [The ADVANCE researchers] were testing [gliclazide] to be used as first-line treatment. So their treatments were not as variable as ours. We wanted to test the treatment strategy that would be used in clinical practice by a typical physician. … Furthermore, they were targeting an HbA1c of <6.5%, and we were targeting <6%,” she said.
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According to George Bakris, MD, FASN, FAHA, director of the Hypertensive Diseases Unit at the University of Chicago-Pritzker School of Medicine, ADVANCE is a trial that got involved early to prevent progression, and ACCORD intervened to try to reduce events in patients who had already progressed.
“There was a very positive outcome in ADVANCE because the interventions were affecting known cardiovascular risk factors, and they were catching it at a time where pancreatic function was still pretty good, where blood pressure was intervened with … so there was markedly reduced risk, and as a result benefits. “ADVANCE and ACCORD are two opposite sides of the spectrum,” continued Bakris, a member of the Endocrine Today editorial board. “On one side, you have very early disease where you are intervening and the results are gratifying. No one is really shocked about that. On the other hand, you have advanced disease where you are intervening too aggressively. The [ACCORD researchers] thought it would be better, but it was not.” Epidemiology dictates that the higher the HbA1c, the greater the cardiovascular risk. “That’s true, but it does not mean that reversing it necessarily reverses all that risk if you get too low,” Bakris cautioned. “That’s the point that is missed in this whole analysis.”
Lessons for clinical practice
The data are too early to suggest a change in the standard of care, according to Bakris.
“In advanced diabetes, should you aggressively intervene to get the blood sugar towards normal? No — not because it is not necessarily good but because there are consequences to trying to get the blood sugar too low, and those consequences are not totally appreciated yet. Perhaps the ADA’s guidelines of HbA1c of <7% is really what we should be striving for and not getting it down to 6%.”
Friedewald hopes that through the overwhelming attention focused on the mortality outcomes, clinicians can still recognize the many positive aspects of the ACCORD trial.
“Mortality was not our primary outcome variable. The thing we were mainly looking at was a combination of mortality plus cardiovascular mortality, nonfatal MI and stroke. There was benefit having lower HbA1c, but it was not statistically significant and certainly didn’t outweigh the increased mortality, which is why we stopped the study,” he said.
“It is very important that we continue to research new treatment strategies,” Hamet added. “If you look at ADVANCE, there is so much less mortality than there was in the UKPDS [UK Prospective Diabetes Study] group. Stroke is decreased, overall mortality is decreased. In the last 15 years, we have improved the morbidity and mortality of diabetes nearly threefold. That’s the good news.
“There are still things to do, there is still room for improvement, but we have really improved a very bad disease to a much less problematic disease. Let’s not just lose what we have gained.” – by Bekah Cintolo
See related article: Where does intensive glucose control stand now, given the study results presented at ADA?
For more information:
- American Diabetes Association. Standards of medical care in diabetes—2008. Diabetes Care. 2008;31:S12-S54.
- Gerstein HC, Riddle MC, Kendall DM, et al. Glycemia treatment strategies in the action to control cardiovascular risk in diabetes (ACCORD) trial. Am J Cardiol. 2007;99[suppl]:34i–43i.
- Goff DC, Ismail-Beigi F, Gerstein H, et al. ACCORD trial study results. Presented at: the American Diabetes Association 68th Scientific Session; June 6-10, 2008; San Francisco.
- MacMahon S, Chalmers J, Patel AA, et al. ADVANCE trial study results. Presented at: the American Diabetes Association 68th Scientific Session; June 6-10, 2008; San Francisco.
- Patel A, MacMahon S, Chalmers J, et al. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-40.