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Target HbA1c levels still the subject of much debate,
but tailored therapy should be the aim
  Their has been much debate over the past 2 years about HbA1c goals for diabetics and much controversy whether a low goal of say 6.3% increases risk for serious negative results like MIs or hypoglycemia. But just this year entering into this debate is the reports from a new study that Lantus, long-acting insulin, or perhaps insulin itself therapt for diabetics might play a role in accelerating already existing cancer cells. Here are links to reports about insulin & cancer followed below with a current discussion about what should HbA1c targets be for type 2 diabetic patients. Jules Levin
Doctors Prescribe Caution With Insulin's Cancer Ties
"This is not definitive, it just alerts us to the possibility" that insulin bolsters cancer risk, Currie said at a press conference. ...
Sanofi to Seek Advice on How to Further Study Lantus: Studies ...
"On the basis of the currently available data, a relationship between insulin glargine andcancer cannot be confirmed nor excluded," the agency said in a ...
The influence of glucose-lowering therapies on cancer risk in type ...
File Format: PDF/Adobe Acrobat - View as HTML
of insulin interacting with these receptors. The cancer risk ... associated with a greater risk of cancer than insulin of human origin. Methods ...
Does diabetes therapy influence the risk of cancer?
Jun 15, 2009 ... The possibility of an association between insulin and cancer ..... of breastcancer in those on insulin glargine alone, although ...
October 9, 2009 | Lisa Nainggolan
Vienna, Austria - Leading diabetes doctors are still discussing where the target for glycated hemoglobin A1c (HbA1c) levels in type 2 diabetes should ideally be set, with one camp calling for a goal of 6.5% or lower, while the other group says 7% or even higher is a reasonable aim. The topic was debated in front of a packed audience at the European Association for the Study of Diabetes (EASD) 2009 Meeting last week and was a hot topic of conversation throughout the meeting.
Currently, the American Diabetes Association(ADA)/EASD guidance states an HbA1c goal of <7%, while other diabetes organizations, such as the American Association of Clinical Endocrinologists (AACE) and the International Diabetes Federation (IDF) have set their HbA1c targets at <6.5%.
The simple message used to be "the lower, the better" when it comes to HbA1c, but the release of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) data last year cast doubt on this and has provoked deliberation ever since. To everyone's surprise, the trial was halted prematurely because of an increased risk of death in patients who underwent intensive blood glucose lowering.
As well as the ACCORD study, the Action in Diabetes and Vascular Disease (ADVANCE) trial, also reported last year, showed a reduction in the progression of albuminuria with intensive glucose control, but there was no effect on cardiovascular-event rates. And intensive blood glucose lowering had no significant effect on the rates of cardiovascular events, death, or microvascular complications in the Veterans Affairs Diabetes Trial (VADT).
Long-term follow-up of the United Kingdom Prospective Diabetes Study (UKPDS), however, did show that a strategy of early intensive glucose lowering had lasting, significant effects not only on major diabetes end points but also on risk of MI or all-cause mortality.
In the wake of all these data, diabetologists are still trying to tease out the best message to convey to primary-care physicians and other nonspecialists who might be treating patients with type 2 diabetes. And although there is still disagreement, a truce of sorts was agreed upon in Vienna: that targeting therapy to the individual patient is the ideal way to approach diabetes management.
Debate centers on older diabetics and lack of data in this group
Much of the debate centers on how to treat older diabetics, as most at the EASD meeting agreed that in younger patients (under 60) with newly diagnosed diabetes, aiming for as low an HbA1c as is possible is the ideal way to try to prevent microvascular complications in the long term.
"Early aggressive treatment to lower HbA1c targets is possible, with little to no risks of hypoglycemia with newer treatment agents."
Older patients, however, will generally suffer from other comorbidities and are most likely to die of cardiovascular disease; also, they may not have enough lifespan left to worry too much about microvascular complications, said the proponents of a 7%-or-higher target. In addition, these older patients often don't want the burden of an intensive glucose-lowering regimen, with the risks associated with polypharmacy and hypoglycemia.
But AACE member Dr Irl B Hirsch (University of Washington Medical Center, Seattle) argued that doctors should be setting their sights on 6.5% or lower "for the majority of patients with diabetes," because "retrospective studies, prospective studies, and epidemiologic analyses support an HbA1c target as close to normal as possible in type 2 diabetes." The risk of hypoglycemia with intensive glucose lowering to levels of 6.5% has been "overexaggerated," he says, adding that "early aggressive treatment to lower HbA1c targets is possible, with little to no risks of hypoglycemia with newer treatment agents."
"We have no studies at all [in those over 70], no randomized clinical-trial data showing us if they benefit from strict glycemic control."
Opposing Hirsch in the EASD debate was Dr Andrea Siebenhofer-Kroitzsch (Medical University of Graz, Austria). She put forward the case for a target of 7% or higher, stating that the "majority of diabetes patients are age 60 or older," and for this group of patients, the clinical-trial data "show little benefit and sometimes harm; none show overwhelming evidence that we have to treat the majority of our patients, who are quite old, to a very low treatment target."
In fact, a new case-control study also presented at EASD and reported by heartwire earlier this week showed that in US veterans with diabetes, an episode of hypoglycemia was associated with a higher risk of MI for the following two weeks and possibly for a few months afterward.
And for those over 70, "We have no studies at all, no randomized clinical-trial data showing us if they benefit from strict glycemic control" or not, Siebenhofer-Kroitzsch told the meeting. Also, CVD "is not prevented by lowering glucose concentrations," so it makes more sense to treat blood pressure and cholesterol than to be glued to the idea of forcing HbA1c levels as low as possible, she noted.
A glucose-centric view of the world
Her colleague Dr Thomas Pieber (Medical University of Graz) added: "We are not saying don't treat diabetes, that's a misunderstanding. But these [older] patients really suffer from cardiovascular disease, and there is no indication whatsoever that you can influence the outcome of CVD by lowering HbA1c below 7%" and "almost no hint" of any benefit in terms of other microvascular outcomes such as retinopathy, nephropathy, and neuropathy, he noted.
"In this glucose-centric view of the world, doctors are fiddling around getting the HbA1c from 7.2 to 6.8 with an additional drug, and meanwhile the BP is much too high, or the patient is still smoking, or they didn't treat lipids," he told heartwire.
But Hirsch disagrees vehemently. Doctors will not overlook BP or cholesterol by focusing on HbA1c, he says. "Certainly that's not what I see in the States. If anything, it's just the opposite, they focus more on the cholesterol and on the BP."
And he takes issue with the premise that all older patients should be managed differently. "In the US, we don't use age as a criterion for not treating aggressively, and that was sort of the assumption made by [Siebenhofer-Kroitzsch and colleagues]. I don't buy that, I don't buy that at all," he told heartwire.
"In the US, we don't use age as a criterion for not treating aggressively."
"We have large numbers of elderly patients. I think percentagewise, it's not as many [as in Europe], because of all the young patients we are seeing due to the obesity epidemic." But "the bottom line is that if someone has a 10- to 20-year life expectancy and they are 65 or 70 years old, I'm not going to use their age as a criterion not to be aggressive with their diabetes."
Are AACE and IDF too extreme, or ADA and EASD too conservative?
AACE secretary Dr Alan Garber (Baylor College of Medicine, Houston, TX) told heartwire in an interview that their target of 6.5% or less "is based largely upon the findings of the UKPDS study with respect to the elimination of excess microvascular risk." He points out that the IDF also has this target. "What is the goal of diabetes management? That goal is to eliminate the complications of diabetes, we believe. If that's the case, based upon the UKPDS, one would logically come to the conclusion that 6.5% is a good target."
"Pushing forward to a lower target to prevent microvascular at the even plausible expense of cardiovascular complications is practicing ahead of the data."
Garber also contends that how blood sugar is lowered is important, that side effects are substance-specific. "The old ADA goal of <7% is largely based on the diabetes control and prevention trial of 1993 and essentially represents the limit function of how good a job you can do controlling the blood sugar using conventional animal insulins," he explains. "Certain European countries are using insulins with a high potential of hypoglycemia, which they are using because they are not in favor of the analogs that have lesser risk of hypoglycemia. Then maybe you have to adjust your targets. But in so doing, these physicians are knowingly accepting some increase in microvascular risk."
Dr Darren McGuire (University of Texas Southwestern School of Medicine, Dallas), a cardiologist who specializes in treating diabetes, told heartwire he sides with the more conservative ADA/EASD stance on this. "My take on the literature is that I don't personally believe we have any data to support a target lower than 7%. When atherosclerotic vascular disease events occur four times more commonly than microvascular, pushing forward to a lower target to prevent microvascular at the . . . expense of cardiovascular complications is practicing ahead of the data."
Lower targets or reasonable targets-that is the question
Hirsch told heartwire that another reason for lobbying for 6.5% is that in aiming for perfection it's more likely that modest treatment targets will be met. In everyday practice, primary-care doctors are never able to get to target, so if doctors are aiming for 7%, the HbA1c levels their patients are able to reach will be around 7.5% or 8%, he noted. But if the goal is 6.5% or less, there is more likelihood of achieving an HbA1c level of 7%, he noted.
But editor-in-chief of the journal Diabetologia, Dr Edwin Gale (University of Bristol, UK), says that by setting targets low, there is a real risk that primary-care physicians will overtreat patients. In many countries, doctors in the field are paid per performance for outcomes such as HbA1c, he said, "and then there is a serious risk in the very elderly that we might do more harm than good."
However, "no one is advocating poor glucose control," he added; what is being discussed is an appropriate target for real people, "not blanket advice. This is about the difference between moderate control and perfect control."
"The ADA is a conservative body, but in this case conservatism is the order of the day."
McGuire agrees: "I think [Hirsch's] is a dangerous perspective. Although, on average, few are going to push to truly achieve HbA1c levels less than 6.5%, there will be some who do. And I think that's challenging. Once we endorse it as a clinical culture, whether or not it's evidence-based, the temptation becomes to make it a quality performance parameter, and if you start gauging the performance of physician practice on these non-evidence-based targets, especially when it's a potential harm to the overall population, it's really problematic. The ADA is a conservative body, but in this case conservatism is the order of the day."
Reconciliation: Individualization of therapy is the way to go
In his talk, Hirsch also discussed a new analysis from ACCORD, presented at the ADA meeting earlier this year but not yet published, as reported by heartwire. That analysis suggested that the excess risk of intensive vs standard therapy in ACCORD occurred when the intensive participants failed to reduce their HbA1c in the first year of the trial. This suggests, he says, that some people with type 2 diabetes can very safely achieve HbA1c levels of less than 7%, but that other people, whose HbA1c levels are more difficult to control, may be at risk if they persist with this intensive strategy.
"This is where the topic of individualization comes in," Hirsch stressed.
Dr Yehuda Handelsman (Metabolic Institute of America, Tarzana, CA), vice president of the AACE, told heartwire: "Most experts agree that high glucose is not good. The average normal HbA1c is 5% unless [one is] overweight and obese. One must conclude that, for the majority of patients, the ones without unstable comorbidities, getting their goal HbA1c to as close to normal-defined as less than 6%-without side effects is the preferred goal. Definitely the rest will benefit from a goal of less than 6.5%. There may be a small minority with complex comorbidities and perhaps a short life span that the goal can be more liberal at 7% and above. Finally, the the concept of individualized therapy, tailoring the target to the patient's profile, is key and is what I use in my practice."
Dr John Buse (University of North Carolina, Chapel Hill) agrees. For the elderly, in particular, discussion with the patient is paramount, he said during a press conference at EASD: "I approach it in this way. If a patient believes in living through chemistry, it tips the balance for me. But if not, I've found it futile to twist their arms to take a bucketful of drugs."
"If a patient believes in living through chemistry, it tips the balance for me. But if not, I've found it futile to twist their arms to take a bucketful of drugs."
But reporters in the room said they found this confusing, and wanted to know whether to provide the information that HbA1c targets should be 6.5%, 7%, or 8% for such patients.
"I know this is an unwanted message, that things are more complicated, but there's no simple answer for treatment targets," Pieber said. Hirsch agreed: "People want simple sound bites, but unfortunately this particular topic is not a simple sound bite."
In conclusion, Gale, who was one of the moderators of the debate between Hirsch and Siebenhofer-Kroitzsch, said: "One of the features of a good debate is that while you listen to each speaker you are totally convinced, then at the end you are totally puzzled. I suspect that if we sat our two discussants down over a coffee, the real differences, when it comes to how they would treat patients, are probably much less than it might appear."
Related links
Hypoglycemia associated with increased risk of MI among US veterans with diabetes [Lipid/Metabolic > Lipid/Metabolic; Oct 05, 2009]
Modest glucose control may be best for diabetic patients with heart failure [Heart failure > Heart failure; Jul 20, 2009]
Intensive glycemic control not directly linked to excess cardiovascular risk [Lipid/Metabolic > Lipid/Metabolic; Jun 10, 2009]
Intensive glucose control reduces MI and CHD-event risk, new meta-analysis shows [Lipid/Metabolic > Lipid/Metabolic; May 21, 2009]
VADT published: Intensive glucose control fails to reduce cardiovascular events [Lipid/Metabolic > Lipid/Metabolic; Dec 18, 2008]
What are the clinical implications of ACCORD/ADVANCE? [Lipid/Metabolic > Lipid/Metabolic; Jun 12, 2008]
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