A recent systematic review by Kelly et al in the Annals of Internal Medicine tackled the issue of glucose control and cardiovascular disease risk in type 2 diabetes.(Annals of Internal Medicine,15 September,2009,vol 151, no 6 p 384.) The authors found by combining data from 28,000 patients from 5 large randomized trial that there was an approximate 10% decrease in the risk for coronary heart disease (largely from decrease in non-fatal myocardial infarctions) but no overall effect on cardiovascular or all cause mortality.The authors' take on the situation is that since there is no apparent benefit from tight control in terms of overall mortality or cardiovascular disease mortality and the risk of serious hypoglycemia is real that the emphasis should be on total risk reduction in terms of optimal control of blood pressure and cholesterol and use of aspirin because in part those maneuvers have been shown to significantly reduce cvd and all-cause mortality.
In the last year, three studies have been published which seem to dash the hopes of those who hoped for a significant decrease in cardiovascular risk by tighter glucose control. Two trials ( ADVANCE and VADT showed no decrease in CV events with tighter control and one trial has even worse news.The ACCORD trial found an increased risk for CV deaths and total mortality in the group treated with intensive glucose control.(more comment on that trial below)
I thought it would be a good time to reprint a commentary I previously made on that general theme.
The following is a slightly re-edited version of comments I made two years ago.
How many evening diner,CMEoid sessions included the chant, "treat to goal,treat to goal" in regard to blood sugar. As with LDl cholesterol-the goal just kept getting lower and lower.
The DPPT study seemed to provide very good evidence that the microvascular complications of type 1 diabetes could be significantly mitigated by "good"control of blood sugar.Later a follow up report from that landmark trial also provided some reasonable evidence that perhaps macrovascular disease could also be decreased.
Many had hoped that we could accomplish the same reduction in the complications of type 2 diabetes by a similar surge of intensive treatment aimed at bringing about near normoglycemia. Would that life and disease and managing disease were so simple.
The DPPT was a fairly simple trial. There were patients with a disease that seems fairly homogeneous and has relatively straightforward pathophysiology ,i.e insulin lack from the clinical beginning and the treatment intervention was simply more insulin. On the other hand, the UKPDS trial involved several treatment arms and greater heterogeneity of comorbid conditions in the subjects as well as more variation in the the tempo of the various pathophysiological disturbances and the fact that the pathophysiology of type 2 is much more complex than in type 1 and is still being worked out, as exemplified by the recent surge of interest in the role and therapeutic manipulation of the incretin family in type 2.
With trials with more complicated conditions and multiple treatment arms there is greater likelihood of chance and confounding and various biases clouding the results. Clouded results or not the UKPDS became a major element in the argument to treat to lower blood glucose value in type 2 diabetes. The results of the UKPDS were not earth moving but were encouraging. There was some decrease in blood vessel disease on retinal exam and some decrease in the rate of progression of urinary protein leak but no change in renal failure or blindness or clinical manifestations of macrovascular disease. The benefit in terms of reduction of retinal microvascular and perhaps renal disease was arguably balanced by an almost four fold increase in serious hypoglycemia episodes ( 0.6% per year versus 2.3%). The former effect was emphasized and the later effect was not in the 2002 position paper from the American diabetes Association from which a lot of the enthusiasm for tight control arose.
Now fast forward to the ACCORD trial . Here is the announcement of the cancellation of the intensive treatment arm of this large randomized trial. This was supposed to be the trial that would answer-among other questions- the question "can we decrease the macrovascular events associated with type 2 diabetes with intensive blood glucose control ?" Here the treatment goal was a HbA1C of less than 6 %, i.e. basically normal.
However,there were more overall deaths in the intensive treatment arm than in the standard treatment arm. Of those intensively treated about 1/2 had hemoglobin A1C values of less than 6.4 while in the standard treatment arm 1/2 had value less than 7.5. The mortality increase was certainly not what the investigators likely expected.The overall death rate was reported as 20% higher but there were actually fewer heart attacks in the intensive treatment arm but of those there was a higher mortality. So what is happening to cause increase mortality? The NIH announced their analysis so far has not determined what factor(s) are to blame.
Is this simply a matter of getting the glucose too low? Maybe, but an early report from the trial claimed that the excess mortality was not related to hypoglycemia although there were expectedly more hypoglycemia episodes in the intensive treatment group. Although rosiglitazone's role in the disappointing results has been battered back and forth the authors of the current Annals review comment that rosi was more commnly used in the intensive arm than in the control arm of ACCORD.
Dr. RW suggested that excessive insulin use may really be the culprit though not necessarily by precipitating hypoglycemia episodes but by fueling weight gain and the metabolic syndrome and insulin resistance. Other suggestions have been made,see here for references, including the stress placed on patients to achieve a difficult therapeutic goal and the theory that too rapid decrease in blood glucose might have played a role.
Various commentators have had their say regarding this trial and some have attempted to give it a bit better spin,but deaths are not a surrogate measure and the major observation of more deaths with intensive treatment may well shift the momentum of diabetic treatment from "lower is better" to "well maybe not too low" and maybe " not necessarily the same target for everyone". A number of doctor bribe programs (A.K.A. pay for performance ) are keyed to hemoglobin A1C levels .Will we see those third party payers whose interests are claimed to be in improving quality of care quickly revise their guidelines?
Physicians want better treatments for their patients and they want results of promising treatments to be true. That desire to do good for their patients coupled with big pharma funded hype often aided by a shinny veneer pasted on by academic and other thought leaders can really energize therapeutic exuberance that may have a much less robust evidentiary base that we were lead to believe.Treating to a goal or treating the numbers can make clinical life seem simpler, sometimes too simple. Of course, an A1C target was just to handy for guideline writers to ignore.
It is a good thing we quasi- codified all some things into guidelines and pay-for-compliance programs otherwise we might not have had a chance to use them before we decided there weren't really a great idea after all. I remember as house officers we used to talk about the patient dying but the electrolytes were in balance but in those days our actions were not guideline driven.
The plan to decrease cardiovascular disease morality by tight blood glucose control may not have been completely abandoned at this juncture but it is hard to locate statements as enthusiastic as the 2002 ADA position paper.
The 2006 ADA position paper offers an approach to use of the hemoglobin A1C that seems reasonable and
and allows for more nuanced clinical judgment, so do the October, 2009 recommendations of the ACCE/ACE (see here.) Here is a quotes from their recent publication emphasizing the increased risk for patients with a longer history of diabetes and implying that one size for the hemoglobin A1C may not really fit everyone.
".....the risk of cardiac events
and death is more common in patients with hypoglycemic
episodes (and especially severe hypoglycemia) and that
the benefit-to-risk ratio decreases progressively with the
duration of diabetes, such that the use of intensive therapy
may be at least relatively contraindicated in patients with
a duration of diabetes longer than 12 years (VADT) (17).
The ACCORD study (15) also suggested that excessively
rapid or aggressive adjustment of therapy may be associated
with increased risk. The A1C levels show an excellent
correlation with the mean glucose level, but this relationship
is also affected by several other factors, such as
hemoglobinopathies, hemolytic anemias, varying rates of
individual glycation, genetics, and the variabilities of different