In contrast, another, larger and longer study, ADVANCE, found no harm and slightly fewer heart attacks in the intensive control group who attained those A1cs of 6.5% over a period of five years.
The full text publications describing both the ACCORD and ADVANCE studies are now available for free and it seems to me they make it crystal clear what killed people in the ACCORD study.
ACCORD is the study that found excess deaths in the group that attained A1cs below 6.5%. ADVANCE did not. You'll find both studies here:
Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. The ADVANCE Collaborative Group. NEJM, Volume 358:2560-2572, June 12, 2008, Number 24
Effects of Intensive Glucose Lowering in Type 2 Diabetes The Action to Control Cardiovascular Risk in Diabetes Study Group.[ACCORD] NEJM Volume 358:2545-2559, June 12, 2008 Number 24
So let's look at what the differences were in how these studies lowered A1c.
You can find out exactly what drugs people took in the ADVANCE study in the supplementary material published with this study.
As you'll see, ADVANCE relied mostly on a sulfonylurea drug, Gliclazide, which isn't available in the US, though in the UK, Australia, and Canada it is considered the best of the sulfonylurea drugs.
Patients who did not get to goal with gliclazide were put on metformin and several other drugs including basal insulin, usually NPH (33% vs 18% on Lantus or Levemir). Only 19% of the participants in the tight control group used fast acting insulin, half of these used R and half analogs.
The actual breakdown of who took what in ADVANCE shows that the preponderance of study subjects (77%) were taking the gliclazide, metformin, or a combination of the two. Only 32 (.6%) of the 5,571 people in the intensive control arm of ADVANCE were taking Avandia or Actos.
Contrast this with ACCORD. You can see what drugs people were taking in ACCORD in this table.
It turns out 4,702 of the 5,128 people in the intensive treatment arm of ACCORD were taking at TZD drug. That's 91.7% of all of them. But here's the kicker: almost all of them--4,677 or 91.2%--were taking Avandia.
I read this and found myself baffled at how many reports on the differences between these two studies I'd read claimed there was no one drug associated with the excess deaths. The disparity between the two studies could not be clearer. One study used almost no Avandia and people who attained tight control had no negative outcomes compared to those with standard control. The other gave Avandia to 9 out of 10 participants in the tight control arm and saw excess deaths.
Yet ACCORD--the Avandia study--is the study doctors and insurers are using to argue that tight control is dangerous and causes heart attacks.
I'm flabbergasted and you should be too. We already knew that Avandia killed people before this study was published. So why wasn't the "Danger" of lowering A1c pinned to the drug people were taking in the study, a drug already known to kill people? And why did the ADA urge patients on Avandia to keep taking it, even after its danger became evident?
I'll let you draw your conclusions, but my guess it has something to do with what drug companies donate what to the American Diabetes Association.
Another bit of information that got lost in the reporting of ACCORD is that the increased risk of excess death in the tight control group was largely found in people who already had experienced heart attacks before the study started--those most prone to heart failure, the condition both Actos and Avandia promote. Among those who had not had heart attacks before the study, the risk of heart disease dropped with tight control.
Two more factors associated with increased risk of negative outcomes with tight control in ACCORD was age over 65 and an A1c at the start of the study that was greater than 8%.
In contrast ACCORD found improvements with tight control for every subgroup of participants.
So now you know why "tight control" CAN be dangerous: It's dangerous when it's achieved using drugs we know can kill people, especially people prone to heart failure, i.e. Avandia and Actos. If you aren't taking these drugs, relax. Lower your blood sugar as much as you want using diet, metformin, gliclazide, and insulin and be secure in the knowledge that you are not going to worsen your risk of having a heart attack.
If your doctor tells you "tight control is dangerous" ask him if he realizes that Avandia was given to over 91% of the subjects in the study that "proved" tight control dangerous.
The other hazard often cited when tight control is discussed is the possibility of serious hypos. So it's worth noting that ADVANCE put people who needed insulin largely on NPH, the notoriously hypo-causing insulin. Even so, during the five years of the study, the researchers found far fewer hypos than they were expecting based on UKPDS. Had they used the more easily controlled newer long acting insulins, they might have seen even fewer hyps than they did.
The breakdown of insulins used wasn't published in the ACCORD study.
We'll return to what ELSE these studies found in future blog posts.