By LAURAN NEERGAARD; and RANDOLPH E. SCHMID The Associated Press WASHINGTON — The government abruptly halted aggressive treatment in a major study of diabetes and heart disease after a surprising number of deaths among patients who pushed their blood sugar to near normal levels, findings that call into question a growing movement in diabetes care. Wednesday's move doesn't affect health guidelines for most Type 2 diabetics, but it raises concern about a particularly vulnerable group: Patients at especially high risk of heart attack or stroke. The study of about 10,000 patients, ACCORD, was supposed to answer a big question: Could pushing blood sugar to near-normal levels, below today's recommended target, help protect these high-risk patients' hearts? Instead, the National Institutes of Health (NIH) took the rare step of halting part of the study 18 months early, citing 257 deaths among aggressively treated patients compared with 203 among diabetics given more standard care. That translates into an extra three deaths for every 1,000 participants a year, and researchers were at a loss to explain why.
The Associated Press
WASHINGTON — The government abruptly halted aggressive treatment in a major study of diabetes and heart disease after a surprising number of deaths among patients who pushed their blood sugar to near normal levels, findings that call into question a growing movement in diabetes care.
Wednesday's move doesn't affect health guidelines for most Type 2 diabetics, but it raises concern about a particularly vulnerable group: Patients at especially high risk of heart attack or stroke.
The study of about 10,000 patients, ACCORD, was supposed to answer a big question: Could pushing blood sugar to near-normal levels, below today's recommended target, help protect these high-risk patients' hearts?
Instead, the National Institutes of Health (NIH) took the rare step of halting part of the study 18 months early, citing 257 deaths among aggressively treated patients compared with 203 among diabetics given more standard care.
That translates into an extra three deaths for every 1,000 participants a year, and researchers were at a loss to explain why.
Very odd.
Diabetics' blood sugar wasn't too low, a condition known as hypoglycemia. And a close look at the multiple medications patients used, including the drug Avandia that is suspected of being heart-risky, showed no sign that any were to blame.
Pioglitazone. Repeat after me. TZDs are third line.
Half the patients were treated with conventional drugs and lifestyle modifications targeted at reducing their blood levels of sugar to 7 to 7.5 percent, the level most commonly targeted by physicians. The other half received the same drugs, but in higher doses and multiple combinations, to reduce sugar levels to about 6 percent, the same level as in healthy individuals. Most had levels of about 8.2 percent at entry into the study, a little higher than the average diabetic. Dr. Irl Hirsch, a diabetes researcher at the University of Washington, said the study's results would be hard to explain to some patients who had spent years and made enormous efforts, through diet and medication, getting and keeping their blood sugar down. They will not want to relax their vigilance, he said. "It will be similar to what many women felt when they heard the news about estrogen," Hirsch said. He added that organizations such as the American Diabetes Association and the American Association of Clinical Endocrinologists would be in a quandary. Their guidelines call for blood-sugar targets as close to normal as possible. And some insurance companies pay doctors extra if their diabetic patients get their sugar levels very low. The patients receiving intensive treatment will be switched to standard treatment as soon as possible, said Dr. Elizabeth Nabel, director of the National Heart, Lung and Blood Institute. The findings contradict previous research suggesting that the lower diabetics can make their blood sugar, the better. That had specialists cautioning Wednesday that it's too soon to know if the finding among heart patients was a fluke or a sign of how exquisitely tailored to each patient's risk factors diabetes care must be. "Everything else has suggested, for 50 years or more, that tight control was good," said Dr. James Dove, president of the American College of Cardiology. "We've got half a century of literature that is put on the back burner right now by one study. ... It may not be the final decision." Some 21 million Americans have diabetes, meaning their bodies can't properly regulate blood sugar, or glucose. Diabetics already are at increased risk of heart disease. Type 2 diabetes, the most common form, is linked to obesity, which in turn harms the heart. Plus, high blood sugar over time damages blood vessels.
Dr. Irl Hirsch, a diabetes researcher at the University of Washington, said the study's results would be hard to explain to some patients who had spent years and made enormous efforts, through diet and medication, getting and keeping their blood sugar down. They will not want to relax their vigilance, he said.
"It will be similar to what many women felt when they heard the news about estrogen," Hirsch said. He added that organizations such as the American Diabetes Association and the American Association of Clinical Endocrinologists would be in a quandary. Their guidelines call for blood-sugar targets as close to normal as possible. And some insurance companies pay doctors extra if their diabetic patients get their sugar levels very low.
The patients receiving intensive treatment will be switched to standard treatment as soon as possible, said Dr. Elizabeth Nabel, director of the National Heart, Lung and Blood Institute.
The findings contradict previous research suggesting that the lower diabetics can make their blood sugar, the better. That had specialists cautioning Wednesday that it's too soon to know if the finding among heart patients was a fluke or a sign of how exquisitely tailored to each patient's risk factors diabetes care must be.
"Everything else has suggested, for 50 years or more, that tight control was good," said Dr. James Dove, president of the American College of Cardiology. "We've got half a century of literature that is put on the back burner right now by one study. ... It may not be the final decision."
Some 21 million Americans have diabetes, meaning their bodies can't properly regulate blood sugar, or glucose. Diabetics already are at increased risk of heart disease. Type 2 diabetes, the most common form, is linked to obesity, which in turn harms the heart. Plus, high blood sugar over time damages blood vessels.
Reddy .. any thoughts ... ?
I'll have to read the ACCORD protocol.
http://www.nhlbi.nih.gov/health/prof/heart/other/accord/q_a.htm#why_changed
DrMurdoch:Pioglitazone. Repeat after me. TZDs are third line.
Pioglitazone is Actos, I'm pretty sure.
Why would you make the TZD's 3rd line? I don't understand your thinking.
Erick
because metformin and the sulfonylureas are better and safer !
yes pioglitazone is actos.
DrMurdoch:because metformin and the sulfonylureas are better and safer !
I guess I am asking WHY you have come to your above quoted conclusion. The article seems to exonerate the TZD Avandia, and there has been no suspicion of Actos, so far. In fact they are careful to say that no med seems to be the culprit, rather the tight glucose control itself.
There seems to be little argument that better DM II control has been of benefit to Diabetics. And many more people are on oral meds.
I am having trouble rationalizing even potential mechanisms for the result of this trial, given that there is no hypoglycemia reported. The best I can do is that there has been some "resetting" of the body's "normal" after some time with Diabetes, and that glucoses between 55 to 110 are "too low" much as Malignant Hypertension cannot be treated by normalizing the pressure too quickly. But this effect has nothing to do with the meds used to treat the Hypertension, only the relative change in pressure.
I cannot find a reason to blame TZD's in the study you are quoting, and so I will accept that YOU are of the opinion that TZD's are risky. But if I were diagnosed with DM II today, it would be the first medicine I would put myself on, until some more evidence is to come out to convince me otherwise.
But I know you may prove correct, I just don't see how/why you have come to the conclusion. It would be ironic, wouldn't it, if Avandia (rosiglitazone) ended up causing more cardiovascular disease because it worked faster and ultimately better than Actos?
I just think it's interesting fodder for discussion.
This study was not designed to assess the safety of TZDs.
Other studies should direct you towards using the more established medications before TZDs.
If a study were done that showed tight control with exercise and dieting did not cause excess cardiovascular deaths, then one would start to wonder if the medications were somehow responsible.
Graham http://www.synapsedirect.com/ Synapse - the EMR for smart users
Never Mind the TZD debate.
The odd finding here is that aggressive glucose lowering caused more deaths, in the short term.
Hard to make sense of it.
I am calling some of my diabetics in to discuss being slightly less aggressive.
Before one generalizes ( again ) and call on ALL their patients to keep their HbA1C above 7 and God forbid advise to keep the HbA1C above 8, please read the comments of these experts here:
http://www.nhlbi.nih.gov/health/prof/heart/other/accord/index.htm
1. The study was designed on patients with established CAHD, or 2 risk factors on patients that carry a diagnosis of Type 2 Diabetes Mellitus of more than 10 years, and keeping the HbA1C within the normal range.
I will not ignore microvascular disease prevention with tighter control. I agree with Graham that when we advise strict blood glucose control, it is not thru medications, but with aggressive lifestyle modification - exercise (per the recent ACSM recommendation - exercising on most days - 5 to 6 times a week etc), weight loss and diet.
2. The bias on TZD's may have probably have exonerated these group.
So Jason aka Murdoch, what will you tell your patients, go ahead continue your lifestyle and let's keep your HbA1C above 7 or 8?
Will you stratify the very old, and those with the diagnosis of Type 2 DM of more than 10 years before you apply the ACCORD trial?
What about those who are controlled tightly for 5 to 10 years and were doing okay, will you withdraw their medications? If they develop neuropathy its okay we have more medications for that? Nephropathy - its okay we have dialysis? Retinopathy - we have Laser? I do not want you to die, just be blind, unable to pee and in pain?
I'm not sure what to do. In general, depending on the patient, I still aim for A1Cs of 6-7. I do aim for 6 when it looks feasible. I am going to be less likely to add more meds for older patients (and aim for 6) with established diabetes and their A1Cs are a wee high, say 7-7.5pct. A1Cs of 8 or higher certainly irk me, I'll always be trying something at that level.
Since walking dramatically reduces Alzheimer's Disease and Diabetes, I still plug it alot :)
The Good TI people weighed in on this topic.
http://ti.ubc.ca/en/letter68
InfoPOEMs® - Presented by cma.ca
Title:
Intensive control of blood sugar (HbA1c < 7.0%) in DM2 may be harmful (ACCORD)
Clinical question:
Does intensive control of blood sugar (HbA1c < 7.0%) improve outcomes in adults with type 2 diabetes?
Bottom line:
Intensive control of blood glucose levels in type 2 diabetics (glycated hemoglobin level < 7.0%) may reduce the incidence of disease-oriented outcomes, but multiple studies have failed to demonstrate any significant reduction in the incidence of adverse patient-oriented outcomes. In this study, intensive control actually increased the incidence of all-cause mortality. Metformin significantly reduces the risk of both major macrovascular events and all-cause mortality and should remain the treatment of choi ce for lowering blood sugar in type 2 diabetics. There is no evidence that significantly demonstrates improved patient-oriented outcomes for any other diabetic drug classes, including insulin.
(LOE = 1b)
Reference:
Gerstein HC, Miller ME, Byington RP, for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.
Study design:Randomized controlled trial (double-blinded)
Funding:Foundation
Allocation: Uncertain
Setting:Outpatient (specialty)
Synopsis:
Previous studies of type 2 diabetes have not reported any significant patient-oriented benefits for intensive control of blood glucose levels, regardless of treatment modality (Shaughnessy AF, Slawson DC. BMJ 2003;327:1-7). The present investigators identified 10,251 adults, aged 40 to 79 years, with type 2 diabetes and a median glycated hemoglobin level (HbA1c) of 8.1%. Eligible subjects randomly received (uncertain allocation concealment) either intensive therapy (targeted HbA1c < 6.0%) or standard therapy (HbA1c from 7.0% to 7.9%).
Treatment regimens were individualized by standard diabetic medications at the discretion of patients and their clinicians. Complete follow-up occurred for 99% of subjects for a mean of 3.5 years. The individuals who measured all outcomes remained blind to treatment group assignment. By intention-to-treat analysis, at 1 year HbA1c levels were significantly lower in the intensive-therapy group compared with the standard therapy group (6.4% vs 7.5%, respectively). Lower HbA1c levels in the intensive-therapy group were associated with higher medication use from all diabetic drug groups.
However, as a result of an increase in all-cause mortality in the intensive-therapy group compared with standard therapy (257 vs 203 deaths, respectively), the study was discontinued. Subjects in the intensive-therapy group also had a significantly increased rate of hypoglycemia, weight gain, and fluid retention.
Another study published in the same journal issue (The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-72) also evaluated the benefit of intensive-control (HbA1c of 6.5% or less) compared to standard therapy (HbA1c from 7.0% to 7.9%) in 11,140 adults with type 2 diabetes.
Although intensive-control significantly reduced the incidence of disease-oriented microvascular events (primarily nephropathy), intensive control did not significantly reduce any patient-oriented major macrovascular events (including death from cardiovascular causes or all-cause mortality). Severe hypoglycemia was again significantly more common in the intensive-control group.
Copyright © 2008 Canadian Medical Association, All Rights Reserved.
Jason, so based on that trial how will you change your management? Will you keep your patients HbA1C above 7? The ACC stood by a target of below 6.5.
Your main concern is Macrovascular in your diabetics? Was it not that ACCORD was a landmark trial in terms of diabetics more than 10 years (I vaguely recall)? Could it be that endothelial damage have already occurred and may explain their findings? Will this same principle apply to those recently diagnosed or those with IFG?
Too many hard questions.
Rogerven: Jason, so based on that trial how will you change your management? Will you keep your patients HbA1C above 7?
Jason, so based on that trial how will you change your management? Will you keep your patients HbA1C above 7?
No. I said previously I am not sure. I think one thing I am going to watch for is I will have less tolerance for hypoglycemia when getting an A1c below 7. I have treated diabetes aggressively for a long time. Admittedly I am more aggressive in younger patients and when the medication choices are easier (ie. metformin only).
The ACC stood by a target of below 6.5.
Opinion. Not necessarily wrong.
Your main concern is Macrovascular in your diabetics? Was it not that ACCORD was a landmark trial in terms of diabetics more than 10 years (I vaguely recall)? Could it be that endothelial damage have already occurred and may explain their findings?
Maybe.
Will this same principle apply to those recently diagnosed or those with IFG?
No. entirely different population. My plan for this group is lots of Metformin early, especially if they fail my "you have to lose 10 lbs of weight or you are going on pills !". I love love Metformin. I also bent my 7 year rule on sitagliptin as I had too many patients needing either a TZD or go on insulin.... many chose sitagliptin. All have tolerated it well and have had improvements in their A1cs to the point I said they didnt need insulin (yet!). I really need some outcome evidence on sitagliptin .. I want it to be my second line drug, after metformin, but I think it will remain behind the sulfonylureas until I see more data. I doubted TZDs from Day 1 when I heard about the fluid retention problems. I can't find many negative trends with the gliptins. Can you ?
Jason,
I tell my patients the following.
1. There are no drugs to date that CURES diabetes. The medications only controls blood sugar. Some promises weight loss, but it is not sustained even with Byetta.
2. Type 2 diabetes can be reversed early in its course. In time the 9 loci identified in the chromosomes of diabetics may hopefully guide us with treatment, natural history or course of disease. Meanwhile, the only way to reverse this condition is EXERCISE (high intensity, frequency and duration), DIET and WEIGHT LOSS.
3. The known risk of diabetes - BE EXPLICIT. Stroke or losing vision or limb leading to dependence is one of the common motivation to modify their lifestyle for patients in my practice.
4. If they continue their lifestyle, I tell them thank you for your patronage. Instead of seeing them once a year it will be every 3 months. 1 visit vs 4, times co pays.
My observation with Glitazones is that the more than 5 year diabetic seem to have more trouble. Gliptins so far I have no problems. I prefer Byetta as it seems to curb the appetite more than the oral one.
As a Medicine man I like to believe that my drugs do everything but that is not the case. It is a team work effort, of lifestyle modification. I state the facts and concern that the future of Medicine with its shrinking reimbursement is to further fragment the system. I have already seen several cases, wherein a Diabetic is seen by at least 3 MD's, and each one have no time to communicate effectively. On one of my case he had 8 for years. I will not bore you with the details