How Low is Optimal and Does it Matter How You Get There?
A Discussion of the ACCORD and ADVANCE Studies
This month the results of two very large clinical studies were released that have led to questions by doctors and patients on the optimum goal for lowering blood sugar in Type 2 diabetes. The results of the two studies are paradoxical and not necessarily consistent with past thinking. In this article I will provide some review of the tools doctors use to monitor blood sugar in diabetes and hopefully offer some clarity on recent study findings. How the results of these studies affect, or do not affect, your health care should be a conversation between you and your doctor and depend on numerous factors.
How is Blood Sugar Monitored?
Because blood sugar levels change from minute to minute, one isolated blood sugar reading has limited value to your or your doctor. For this reason your doctor or diabetes educator looks for trends in your blood sugar logs to determine the general range of your blood sugar and uses these trends to determine, in the short term, whether you have responded well to a change in diet or treatment. However, other tests of blood sugar are also used that give a more objective idea of how your blood sugar ranges over time; this measure is called the hemoglobin A1c (HbA1c or A1c) and is reported as a percentage (%). The A1c is a measurement of how much sugar has stuck to proteins in your blood cells (See Complementary Corner December 2006 for more discuss on this process) and provides a measurement of average blood sugar over approximately 3 months. The current recommendation (by the American Diabetes Association) is to try to get A1c less than 7%. Hopefully your doctor shares this number with you every few months, and if not, you should ask to know your numbers.There really is no reason to be surprised by your A1c results from your doctor if you are monitoring your blood sugar in the morning and 2-hours after meals. An A1c of 7% is approximately equal to an average blood sugar of 170 mg/dL, with each 1% increase corresponding to an increase of 35 mg/dL in average blood sugar, e.g. a A1c of 8% = 205mg/dL on average.
Why A1c is Important: Evidence from Past Studies
I try to spend as much time with my patients as possible, explaining to them what their lab results mean and why the results are important to treatment, however I know this is not common practice for all doctors. A common complaint I hear is “All my doctor does is treat my numbers by writing me a new prescription - and I don’t know what any of it means.” I think it is important to understand your A1c and why it is important, so I hope this explanation is helpful:
A large study called the United Kingdom Prospective Diabetes Study (or UKPDS) gathered together over 4500 people with diabetes and followed them for fifteen years (Stratton et al., BMJ, 2000). One group was treated “intensively” and the other group was treated “conventionally”; after 15 years, the results showed that for every 1% reduction in A1c there was about a 25% reduction in complications like retinal disease (retinopathy), kidney disease (nephropathy) and nerve disease (neuropathy). One of the strongest findings was a 33% reduction in a marker of kidney function called albuminuria (a measure of protein loss by the kidneys). Additionally heart attacks and cataracts also appeared to be reduced, but these results were not very strong.
So the UKPDS demonstrated that blood glucose control is important to prevent the small vessel (microvascular) complications of diabetes and A1c levels actually represent risk very well making A1c a very useful test to track the progress of patients. The UKPDS did not show definitively that lowering A1c resulted in lower risk for large vessel (macrovascular) complications like having a heart attack; this question remained unanswered.
Also unanswered were questions about the optimal level of A1c. Although half of the people in the UKPDS were treated intensively, their average A1c was still almost 8% at the end of the study. Whether or not additional protection was gained by lowering blood sugar, and therefore A1c, further was unknown.
Recent Studies: ACCORD and ADVANCE
Two studies were just released this week that were designed to help answer these remaining questions- and they may or may not have succeeded.
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study followed 10,250 people with Type 2 diabetes and aimed to compare the effects of reducing A1c to the normal range (less than 6%; intensive) using oral drugs and insulin compared to standard levels of control (7.0-7.9%; standard). The people who participated in the study were considered “high risk” because they were required to have known heart disease, kidney disease, heart enlargement or two risk factors (elevated cholesterol, elevated blood pressure, smoking or elevated body weight). The ACCORD trial was stopped early after 3.5 years because more deaths were occurring in the intensive group (257 vs. 203, or a 22% increase in risk)! This finding was highly unexpected and has been difficult to explain. When the study was stopped, the average A1c was 6.4% in the intensive group and 7.5% in the standard group. (The ACCORD Study Group, NEJM, 2008)
The ADVANCE study followed 11,140 people with Type 2 diabetes for 5 years and also sought to compare the results of intensive (A1c less than 6.5%) blood sugar lowering to more standard lowering (A1c less than 7%). The people who participated in the ADVANCE study were lower risk than those in ACCORD; in order to participate in ADVANCE people were required to have either heart disease, small vessel complications or one risk factor (elevated cholesterol, elevated blood pressure, smoking or elevated body weight). The ADVANCE trial was completed according to its normal schedule and was not stopped early.
At the end of the study, no differences were found in death from any cause between the two groups: neither death from cardiovascular disease nor cardiovascular events like development of heart failure or heart attack. The major finding of ADVANCE was a 14% reduction in small vessel, complications the majority of which was a 21% reduction in risk for kidney disease (nephropathy). When the study was completed, the average A1c was 6.5% in the intensive group and 7.3% in the standard group. (The ADVANCE Collaborative Group, NEJM, 2008)
To summarize, these two studies resulted in nearly identical levels of A1c (although this occurred over different periods of time) but had very different results. The ACCORD study suggests it might do more harm than good to aggressively lower A1c in people with known vascular disease or who have multiple risk factors, and offered no evidence of benefit for large vessel disease. The ADVANCE study also offered no evidence of benefit of for aggressively reducing A1c for large vessel disease, but did suggest substantial risk reduction for small vessel complications, especially kidney disease. This finding from ADVANCE is consistent from earlier findings in the UKPDS, i.e. intensive control appears to have greater impact on small vessel disease.
Is There a Good Explanation for These Results?
Unfortunately, the answer is no, not yet. The results of the ACCORD trial are the most confusing for doctors and patients alike- and comparing differences between the two groups in ACCORD offers hypotheses but not answers. For one, more people in the intensive group were treated with thiazolidinedione class medications, including rosiglitazone which has been associated with higher rates of cardiovascular events including heart attack (See Complementary Corner June 2007 for more information). There were also more hypoglycemic events that occurred in the intensively treated group in the ACCORD study. However, according to the investigators of the study, these differences in the two groups in ACCORD do not explain the increased rate of death. (It is important to note however that detecting differences of this type between the two groups was not the original intent of the study and therefore there are significant statistical limitations to detecting real differences. )
So if the result of increased death from lower A1c in ACCORD is true, why didn’t it happen in ADVANCE? There are some notable differences between the ACCORD study and the ADVANCE study. For one, the participants in the ACCORD study had a higher degree of risk at the beginning of the study in order to be included, including a longer duration of diabetes and a higher A1c coming into the study. Thiazolidinedione medications (e.g. Actos and Avandia) were used much, much more commonly in ACCORD. Also there were more hypoglycemic events requiring medical assistance in ACCORD than in ADVANCE due to a much higher number of people being put on high doses of insulin in order to lower their A1c.
What do these Results Mean for Me?
The implications of the results of ACCORD and ADVANCE are still being learned and decisions about how the results may change anything are still being discussed. I think the results tell us the following important things:
1. Good blood sugar control remains important; first know your A1c and continue diet and exercise efforts to reduce it.
2. Great care is warranted when using medications to aggressively lower A1c in patients.
3. Some medications may lower A1c but do not necessarily improve health or lower risk. Every medication should be used after considering the risks and benefits of the medication for the individual patient.
4. Findings have been very consistent that lower A1c lowers risk for small vessel disease and thus lower A1c remains a goal for most patients provided it can be done safely without increasing serious hypoglycemia.
5. Findings remain consistent that lower A1c has a minimal effect of large vessel disease, if any effect at all.
Questions that Remain
As mentioned, both the ACCORD and ADVANCE trial resulted in many questions. My take home message from the two studies has been that it is not only the value of A1c that matters, but also how that value is reached that is important to health in diabetes.
One burning question that remains for me is does a higher A1c, if reached by using diet and exercise with good reduction of other risks (blood pressure, lipids, etc), provide more protection than heavily drug-induced reductions of A1c? What effect does lowering A1c into the normal range (less than 6%) using diet and exercise (if it can be done), even in high-risk patients, have on risk of cardiovascular events and death? These questions remain unanswered.
Until we have answers, in my practice I will continue to use diet and exercise as the mainstay of my treatment of diabetes to get the A1c as low as possible and then switch to the careful and judicious use of drugs after evaluating the risks and benefits of each.
In health- Ryan Bradley, ND, MPH
Ryan Bradley, ND, MPH is a naturopathic doctor, clinical researcher and epidemiologist in San Diego, CA. He is an Associate Professor and Assistant Director of Research at the National University of Natural Medicine in Portland, OR and an Assistant Professor in the Department of Family Medicine and Public Health at the University of California, San Diego.
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