Dr. Weeks’ Comment: Of all the modern illnesses, I hate diabetes the most because it is so insidious – I call it the “Turkey” disease since we carve up the patients. First off come the toes, then the feet then BKA (below knee amputation) then AKA (you figure it out!) and then organ failure. And, please get this, diabetes is very treatable and very preventable.
Re-thinking the Diagnosis of Diabetes: Is A1C the Final Answer?
Gregory A. Nichols, PhD
In July 2009, an international expert committee published a report that made the case for using the hemoglobin A1C assay to diagnose type 2 diabetes. The committee included members appointed by the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the International Diabetes Federation (IDF); the report represented a “consensus view and not necessarily the view of the organizations that appointed them.” The Expert Committee said it hoped that the report “will serve as a stimulus to the international community and professional organizations to consider the use of the A1C assay for the diagnosis of diabetes.”
Since the report was published, members of the international community have convened in Vienna, Austria, at the EASD’s 45th annual meeting and in Montreal, Quebec, Canada, at the IDF’s 20th World Diabetes Congress. From comments expressed at podiums by thought leaders as well as from hallway conversations, it was clear that the Expert Committee had succeeded in its hope to stimulate discussion of the topic. Moreover, as of January 2010, the ADA now includes A1C as an appropriate diagnostic test, reversing its previous position that recommended against it. The ADA seemed to rely heavily on the Expert Committee’s July report in reaching its position, because considerably less detail was included in its recommendation than might have been expected.
Chronic diseases imply damaged or dysfunctional body parts. In the case of diabetes, the dysfunction is in the body’s ability to make or use insulin. Whether diabetes begins with the inability to properly use insulin (insulin resistance) or with inadequate production of insulin (beta-cell failure) is controversial, but most diabetic patients experience both problems earlier rather than later in the disease.[3,4] From the standpoint of diagnosis, however, the origin of diabetes is an academic debate because the use or production of insulin cannot realistically be measured on a population-wide basis. Thus, we rely on the result of the dysfunction — hyperglycemia — to characterize and diagnose diabetes.
In the United States, diagnosis is typically made on the basis of fasting plasma glucose (FPG), while in Europe and in clinical trials, an oral glucose tolerance test (OGTT) is the preferred method. Unfortunately, both tests have rather limited overlap, meaning that most persons diagnosed by an FPG would not be diagnosed by an OGTT, and vice-versa. Furthermore, the 2 tests can produce different results for the same person on different days. As if that weren’t sufficiently confusing, consider that the level of hyperglycemia necessary to diagnose diabetes, by either test, is somewhat arbitrary. Because it is not clear what level of hyperglycemia represents a given level of insulin use or production, diagnosis is based on the point at which diabetic retinopathy becomes markedly more prevalent. Yet neither test is used to manage diabetes once it is diagnosed — for that, we rely on A1C. Given all this confusion, is it any wonder that experts are seeking an alternative to the status quo?
Use of A1C to diagnose diabetes has been considered by expert panels in the past, but the idea has been rejected.[7,8] The primary obstacle was a lack of standardization of the assay, but that is no longer the case. In fact, A1C is better standardized than other measurements of glucose. Other advantages of A1C include the fact that it is a better indication of overall glycemic exposure over time and that there is substantially less day-to-day variability.[10,11] From a practical standpoint, A1C is much easier to measure because it does not require fasting or timed samples, and it is currently used to manage diabetes.
There remain 2 main objections to using A1C to diagnose diabetes, both of which are mostly relevant to middle-income and developing countries. First, the cost of the assay is somewhat higher than that of the FPG or OGTT; however, if one fully accounts for the indirect costs to the patient, these may become negligible. Second, the A1C assay is not available worldwide, meaning that the same person may or may not have diabetes depending on country of diagnosis. Of course, that is no different from the way it is now, given the differential use of FPG and OGTT.
It should also be noted that accurate measurement of A1C depends on the life span of the red blood cell, which can vary substantially and therefore alter the result. On balance, however, the attractiveness of a single test to both diagnose and manage diabetes, especially when the test is easy to administer and largely reproducible, suggests that greater reliance on the A1C assay is inevitable.
If and when A1C becomes an accepted or even preferred test for diagnosing diabetes, the question becomes, At what level should diagnosis occur? Again, it isn’t possible to know — let alone measure — when insulin resistance has become too high for insulin production to compensate for it, or when insulin production has fallen inadequately low. The expert panel followed the methods used to define diagnostic thresholds for the FPG and OGTT, identifying 6.5% as the A1C level at which the prevalence of diabetic retinopathy begins to rise above that of nondiabetic patients. Although the panel noted the studies of Egyptians, Pima Indians, and Mauritians used to select FPG and OGTT cut-points, it also relied heavily on unpublished data from one of the panel members — not a tactic that would survive standard peer review. Noticeably absent from the justification for the expert panel’s decision is any discussion of peer-reviewed studies that have suggested a diagnostic A1C level, perhaps because these have all identified somewhat lower cut-points, ranging from 5.8% to 6.2%.[13-15]
The purpose in making a diagnosis is to initiate treatment. The question, then, is when should treatment of hyperglycemia begin? The success of several prevention trials muddies these waters. Clearly, at-risk patients can substantially reduce their risk of developing diabetes through lifestyle changes or by taking anti-hyperglycemic medications.[16-20] Yet these prevention approaches are, in essence, identical to the treatment of diabetes itself. Thus, one could argue that the prevention trials were merely treating diabetes at an earlier stage.
Whether this “early” treatment reduces the risk for microvascular and macrovascular complications associated with diabetes has not yet been determined. If we subsequently learn that early treatment can reduce those complications, then diagnosis of diabetes (by whatever test) must be made sooner. Even if complications aren’t avoided with early treatment, other benefits of lifestyle can certainly accrue. Thus, there is little reason to delay diagnosis (and treatment) until A1C reaches 6.5%.
Of course, the current treatment goal for patients with diabetes is an A1C < 7%, and recent studies have not demonstrated a clear macrovascular benefit to a more stringent goal, though microvascular risk may be reduced.[21-23] In any case, a diagnostic threshold that is inconsistent with treatment goals would seem to create a disconnect, but this does not need to be so. A newly diagnosed patient whose condition is well controlled at diagnosis may have a better chance of maintaining control over the long run, which can provide long-term health benefits.
Turning to A1C as a diagnostic tool leaves us wondering what to do about the high-risk categories of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). These have been valuable concepts in defining patients at risk for diabetes, especially for the prevention trials that recruited from such groups The expert panel treats this issue in 2 conflicting ways. First, it suggests that an A1C between 6.0% and 6.4% would identify patients at high risk for diabetes (ie, progressing to > 6.5%), so in that sense, those patients would represent a group equivalent to those classified with IFG/IGT. But then the panel argues that categorical classification of subdiabetic hyperglycemia is less than ideal because the risk for diabetes appears to be a continuum. Is there reason to think that is not the case with A1C? If so, the expert panel does not provide the rationale.
Furthermore, once one argues that risk is continuous, how can one argue for a cut-point for defining diabetes? Shouldn’t hyperglycemia — however measured — be viewed as a factor that works in concert with other biological measures to put patients at risk for microvascular and macrovascular complications? There is little doubt that factors other than just hyperglycemia — namely, dyslipidemia, obesity, and hypertension — contribute to the risk of developing diabetes.[25-27] Of course, these same factors increase the risk for complications associated with diabetes, especially cardiovascular disease. No one would argue against the statement that diabetes is a complex, multifaceted disease, and there is evidence that addressing blood pressure and lipids (in addition to hyperglycemia) improves outcomes. After all, which patient is at greatest risk for health problems: patient A, with an FPG of 125 mg/dL but normal blood pressure, weight, and lipid levels, or patient B, with an FPG of just 100 mg/dL but a blood pressure of 145/90 mm Hg and a body mass index of 32kg/m2?
In summary, the expert panel has suggested that the A1C assay be used to diagnose diabetes, recommending 6.5% as the diagnostic threshold, and the ADA has now accepted the suggestion. Incidentally, this was not the first expert panel to examine this issue. In fact, as recently as 2008, another group suggested the very same thing. In that report, the authors noted that up to 50% of doctors were already using A1C to diagnose diabetes. You may be one of them.
Regardless of which test you use, you probably take into account many more factors than just the result of that test in assessing your patients’ health risk and in selecting the best treatment approach. If an expert panel wanted to take on the topic of diagnosing diabetes, perhaps it is time to turn away from the glucose-centric definition to one that more clearly represents the full cardiometabolic risk of the individual patient.
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Arch Intern Med. 2007;167:1545-1551. Abstract 12.Cohen RM, Franco RS, Khera PK, et al. Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c. Blood. 2008;112:4284-4291. Abstract 13.Bennett CM, Guo M, Dharmage SC. HbA(1c) as a screening tool for detection of type 2 diabetes: a systematic review. Diabetic Medicine. 2007;24:333-342. Abstract 14.Buell C, Kermah D, Davidson MB. Utility of A1C for diabetes screening in the 1999 2004 NHANES population. Diabetes Care. 2007;30:2233-2235. Abstract 15.Perry RC, Shankar RR, Fineberg N, McGill J, Baron AD; Early Diabetes Prevention Program (EDIP). HbA1c measurement improves the detection of type 2 diabetes in high-risk individuals with nondiagnostic levels of fasting plasma glucose: The Early Diabetes Intervention Program (EDIP). Diabetes Care. 2001;24:465-471. Abstract 16.Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20:537-544. Abstract 17.Tuomilehto J, Eriksson JG, Valle TT, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350. Abstract 18.Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with life-style intervention or metformin. N Engl J Med. 2002;346:393-403. Abstract 19.Chiasson JL, Josse RG, Gomis R, et al. Acarbose for prevention of type 2 diabetes: The STOP-NIDDM randomized trial. Lancet. 2002;359:2072-2077. Abstract 20.The DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled trial. Lancet. 2006;368:1096-1105. Abstract 21.The Action to Control Cardiovascular Risk in Diabetes Study Group. 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