Controversial question



Will you use HbA1c to screen for type 2 diabetes?




1. L. Czupryniak, Poland


2. S. Duran-Garcia, Spain


3. H. Gawish, Egypt


4. L. Ji, China


5. S. R. Joshi, India


6. E. Mannucci, Italy


7. J. F. Raposo, Portugal


8. O. Smirnova, Russia


9. B. L. Wajchenberg, Brazil




1. L. Czupryniak, Poland


Leszek CZUPRYNIAK, MD, PhD
Department of Internal Medicine
and Diabetology
Barlicki University Hospital No. 1
Medical University of Lodz
Kopcinskiego 22
90-153 Lodz, POLAND

(e-mail: leszek.czupryniak@umed.lodz.pl)

Screening for type 2 diabetes has become accepted policy in the modern world, in which, more often than not, preventive medicine is practised. Using plasma or capillary blood glucose measurements for diabetes screening is an acknowledged procedure. However, the debate about whether fasting or postprandial/postchallenge values should be used for this purpose has never been unanimously resolved. Fasting plasma glucose (FPG) is easier to categorize, while (ab)normal postprandial values will probably never be defined. Yet, fasting measurements only allow you to diagnose diabetes in a third of afflicted individuals.1 The need for a more effective screening tool is therefore apparent.

The potential of glycated hemoglobin (HbA1c) in diabetes screening was first discussed over 30 years ago. HbA1c was found to be elevated only in subjects with both high fasting and postchallenge glucose, and it was concluded that it may help identify subjects with substantially reduced glucose tolerance.2 Since January 2010, HbA1c ≥6.5% has been accepted as a diagnostic threshold for diabetes by the American Diabetes Association (ADA).3 The authors of these recommendations argue that measuring an index of exposure to chronic hyperglycemia is the most logical way to look for glucose tolerance abnormalities. Indeed, measurement of HbA1c has several advantages over plasma glucose assessment. It is stable in acute conditions and might be particularly useful in subjects with acute infections, myocardial infarction, or stroke where stress-related hyperglycemia might occur. It is also resistant to short-term changes in diet, recent exercise, or stressful life episodes.

For HbA1c to be determined, a subject does not have to be fasting, and current analytical methods make it possible to measure HbA1c during a subject’s visit at the doctor’s office. HbA1c value might give an insight into the history of glucose tolerance and capture individual susceptibility to glycation. If it were grossly elevated, then it might prompt diagnostic procedures towards early detection of late diabetes complications. HbA1c has been shown to highly correlate with the risk of CVD in newly diagnosed subjects.4 Furthermore, HbA1c is stable at room temperature, while glucose disappears from blood samples at a rate of 5%-7% per hour.

Measuring HbA1c has, however, some important limitations. Determination of HbA1c is more expensive than the assessment of plasma glucose. In subjects with accelerated (ie, with hemolytic anemia or after acute blood loss) or slowed (eg, after splenectomy) red cell turnover, HbA1c values lose their otherwise linear correlation with plasma glucose. Individuals of certain ethnicities might be affected with structural hemoglobinopathies (eg, the HbE trait found in up to 50% of Southeast Asians), making HbA1c assessment impossible.5 Other conditions influencing HbA1c measurement include uremia, hypertriglyceridemia, hyperbilirubinemia, alcoholism, chronic use of salicylates and/or vitamin C, and opiate addiction. Iron deficiency causes artificial HbA1c elevation by modifying HbA1c structure.6 The analytical method for determining HbA1c must be standardized or traceable to Diabetes Control and Complications Trial (DCCT) reference assays.

Nevertheless, even with the limitations, I would use HbA1c for diabetes screening, with two caveats. First, positive screening results do not necessarily equate to making a final diagnosis. In many cases, a diagnosis of diabetes with elevated HbA1c will have to be confirmed by either repeating the test or using plasma glucose parameters. The ADA recommends confirming positive diagnostic results of HbA1c, fasting glucose, or oral glucose tolerance tests (OGTT) with repeat testing if equivocal hyperglycemia is found.3 Second, the HbA1c threshold value for positive screening is debatable. In cases with high HbA1c levels (>7%), the diagnosis will probably be obvious, but within the range slightly exceeding normal values (6.0%-6.5%), doubts will remain until another test has been performed as HbA1c <6.5% (or even <6.0%) does not exclude the possibility of diabetes, particularly at an early stage. _

References
1. Drzewoski J, Czupryniak L. Concordance between fasting and 2-h post-glucose challenge criteria for the diagnosis of diabetes mellitus and glucose intolerance in high risk individuals. Diabet Med. 2001;18:29-31.
2. Svendsen PA, Jørgensen J, Nerup J. HbA1c and the diagnosis of diabetes mellitus. Acta Med Scand. 1981;210:313-316.
3. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33(suppl 1):S62-S69.
4. Selvin E, Steffes MW, Zhu H, et al. Glycated hemoglobin, diabetes and cardiovascular risk in nondiabetic adults. N Engl J Med. 2010;362:800-811.
5. NGSP Factors that Interfere with HbA1c Test Results. Updated 4/2010. http://www.ngsp.org/factors.asp. Accessed November 26, 2010.
6. Herman WH, Fajans SS. Hemoglobin A1c for the diagnosis of diabetes. Practical considerations. Pol Arch Med Wewn. 2010;120:37-41.

2.Santiago DURAN-GARCIA,Spain


Santiago DURAN-GARCIA, MD, PhD
Hospital Universitario De Valme
Carretera De Sevilla-Cadiz S/N
Sevilla 41014, SPAIN

(e-mail: sduran@duransanz.com)

It has recently been published that “it is reasonable to consider an HbA1c range of 5.7% to 6.4% as identifying individuals with high risk for future diabetes and to whom the term prediabetes may be applied if desired.” Glycated hemoglobin (HbA1c) is a widely used marker of chronic glycemia and plays a critical role in the management of patients with diabetes. Prior expert committees have not recommended the use of the HbA1c test for the diagnosis of diabetes, due to a lack of standardization of the assay. More recently an international committee, after an extensive review of both established and emerging epidemiological evidence, recommended the use of the HbA1c test to diagnose type 2 diabetes, with a threshold of ≥6.5%. The diagnostic test should be performed using a method certified by the NGSP (National Glycohemoglobin Standardization Program). Point-ofcare HbA1c assays are not sufficiently accurate at this time to use for diagnostic purposes. There is an inherent logic to using a chronic marker of dysglycemia rather than an acute one, particularly since HbA1c has several advantages to fasting plasma glucose (FPG), including greater convenience (since fasting is not required), evidence to suggest greater preanalytical stability, and less day-to-day perturbations during periods of stress and illness.

In Spain, as in other European countries, the cost is similar to the determination of baseline glycemia on two different days, with greater convenience for the patient. In patients with abnormal FPG, the need for glucose overloads could be avoided, with the ensuing savings in analytical costs and time invested by patients. Both the Spanish Endocrinology and Nutrition Society (SEEN) and the Spanish Diabetes Society (SED) have recently expressed support for the recommendations of the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the International Diabetes Federation (IDF).3 One debatable point is the impression held by many clinicians that the correlation between HbA1c and mean daily gly-cemia is not entirely linear in some patients. But this does not seem to be preventing us from using HbA1c as a reliable diagnostic tool in the general population. In order to overcome a potential lack of protection in subjects with undiagnosed diabetes, the Endocrine Society has suggested that intensive cardiovascular protection therapy should be initiated in all subjects with an HbA1c between 5.7% and 6.5%, and this recommendation has also been fully accepted by the SEEN and the SED. The documents published recap situations in which HbA1c must not be used as a diagnostic tool or in the assessment of glycemic control (severe ferropenias, hemolytic anemias, thalassemias or other hemoglobinopathies, hereditary spherocytosis, cancer, kidney failure, liver failure, or advanced age). Both societies clearly specify that HbA1c must not be used as a diagnostic tool in type 1 diabetes mellitus, in gestational diabetes,4,5 or in pediatric patients.

The application of this test in the diagnosis of type 2 diabetes, as well as in situations of type 2 prediabetes, may have major repercussions in habitual clinical practice on the pass-on costs in the health system and on the early prevention of the development of vascular complications. It must not be forgotten that, in any case, the goal is to diagnose this condition as early on as possible, which may be easier with the availability of this diagnostic tool. _

References
1. International Expert Committee. The international expert committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care. 2009;32: 1327-1334.
2. American Diabetes Association. Standards of Medical Care in Diabetes—2010. Diabetes Care. 2010;33(suppl 1):S11-S61.
3. Aguilar Diosdado M. Hemoglobin A1c for the diagnosis of diabetes mellitus? Pros and cons. Avances en Diabetologia. 2010;26:4-5.
4. Fernandez I, Hernandez C, Gonzalez MC, Roldan E, Duran S. Determinación de los niveles de hemoglobinas glucosiladas: estudios en pacientes con intolerancia hidrocarbonada y correlaciones clínico-biológicas en pacientes diabéticos. Medicina Clínica. 1983;81:839-843.
5. Duran S, Fernandez I, Guillen R, Costa C. Gestational diabetes: heterogeneity and glycemic control. Duran S, ed. Diabetes & Pregnancy. Seville, Spain: Publications of the University of Seville; 1987:51-64.

3.H. Gawish,Egypt


Hanan GAWISH,MD
Professor of Internal Medicine
Diabetes and Endocrinology Unit
Mansoura University, EGYPT

(e-mail: hanangawish@mans.edu.eg)

Glycated hemoglobin (HbA1c) value and its cutoff level have always been the subject of debates. A target goal of HbA1c ≤7% was recommended by the American Diabetes Association (ADA), while both the American College of Endocrinology (ACE) and the American Association of Clinical Endocrinology (AACE) adopted a lower target of HbA ≤6.5% in 2001. Although HbA1c had been proved to be significantly linked to the risk of diabetes complications, until recently it was not accepted for use in the diagnosis of diabetes. In June 2009, the ADA raised the prospect of making HbA1c essential for the diagnosis of diabetes. A threshold HbA1c of 6.5% or above being diagnostic of diabetes, and levels between 5.7% and 6.4% identifying patients at high risk of developing diabetes and its complications. The ADA’s last report succeeded in starting a debate among professionals internationally.

The effect of ethnicity on HbA1c is going to be of great concern with the shift toward HbA1c-based diagnosis for diabetes. This might necessitate having different HbA1c cutoff values for the diagnosis of diabetes in different populations. An assessment of the impact of ethnicity on HbA1c that compares data and epidemiological studies is expected in the future.

Worldwide debate is mainly based on the cutoff points for diagnosis, which need more evidence to be substantiated. An HbA1c of 6.5% has been unequivocally linked to microvascular complications such as diabetic retinopathy and peripheral neuropathy. It has also been linked to macrovascular complications, increased cardiovascular risk, and carotid intimal thickening with its cerebrovascular insults. This is why it is widely believed that a cutoff HbA1c value of 6.5% for diagnosis is going to underestimate the problem. Diabetologists are willing to intervene early, at least with lifestyle modification and metformin, which are supported by adequate evidence, but an HbA1c cutoff value of 6.5% is going to have the reverse effect.

For developing countries like Egypt, where there is no national program for screening sponsored by the government, other difficulties might come up. The issue of cost is crucial in applying ADA recommendations. The cost of HbA1c testing is around 7 times that of plasma glucose testing in Egypt. HbA1c testing is not routinely available in all laboratories, especially in rural areas. The issues of standardization, quality control, and reproducibility in different labs will be of great concern.

Illnesses interfering with HbA1c assay are of the utmost importance, even if the newmethods of estimation take theminto account. A high prevalence of all types of anemia, including hemoglobinopathies, is present in Egypt. This will add another barrier to the widespread acceptance of ADA recommendations not only in Egypt, but also in other Mediterranean countries.

The advantages of using HbA1c percentage as a diagnostic test for diabetes, as the ADA mention, are its reproducibility and convenience, as fasting is not required. But the disadvantages outweigh these advantages, especially in developing countries.

In conclusion, the utility of HbA1c as a marker for metabolic control cannot easily be extended to validate its use for the diagnosis of diabetes. A consensus with clear answers to all questions raised should be reached before HbA1c becomes widely accepted as a reliable diagnostic tool. _

4.L. Ji,China


Linong JI,MD
Department of Endocrinology
The People’s Hospital of Peking University
11 Xizhimen South Street, Xicheng District
Beijing, CHINA

(e-mail: jiln@bjmu.edu.cn)

The increasing prevalence of diabetes across the world has become a major public health issue of global concern. Early diagnosis and treatment of diabetes is key for reducing the risk of diabetic complications. For a long time, researchers have been looking for easier and more accurate ways of diagnosing diabetes.

In 2009, after reviewing the evidence on the role of glycated hemoglobin (HbA1c) in diagnosing diabetes, an international expert committee jointly organized by the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the International Diabetes Federation (IDF) recommended the use of HbA1c as a diagnostic tool for diabetes, with HbA1c ≥6.5% as the diagnosis cutoff.

Following this announcement, the ADA officially recommended HbA1c as the preferred parameter for diagnosing diabetes, recommending an HbA1c ≥6.5% as the cutoff for this purpose and classifying 5.7% ≤HbA1c ≤6.4% as a high risk category for diabetes as well as cardiovascular diseases. The advantage of HbA1c for the diagnosis of diabetes over the current gold standard based on glucose measurement is well elaborated in the statement of the international expert committee.

Obviously, there are some major reasons in opting for HbA1c : objectivity in reflecting chronic hyperglycemia; high replicability; much greater relevance to cardiovascular events in diabetics; and greater convenience, as there is no need to take into account the time of blood sampling and food intake.

In China, two issues need to be addressed before HbA1c can be recommended as the diagnostic tool for diabetes. Firstly, the HbA1c threshold associated with diabetic complications (in particular diabetic retinopathy) needs to be evaluated to rule out the possibility that the HbA1c cutoff for diagnosing diabetes might be race specific, since a Japanese study shows that the HbA1c risk threshold for significant increased retinal degeneration is 5.7%, which is quite different from the ADA recommended threshold.

Secondly, great effort needs to be taken to standardize the HbA1c testing method. According to a recent survey, there was great variability when measuring the same blood sample among different clinical labs. In addition, the HbA1c assay needs to gain popularity in China since HbA1c has not been widely used in the clinical management of diabetes in the past.

To address these issues, studies are now being undertaken to look for the HbA1c cutoff for diagnosing diabetes and to examine the relationship between HbA1c level and risk of retinopathy in the general Chinese population. A grant program, the China HbA1c Education Program, was launched to educate health-care providers and patients on how to use HbA1c in the daily management of diabetes. Another important part of this program is to educate laboratory technicians to use standard assays of HbA1c in order to provide a high-quality service in diabetes care. _

5.S. R. Joshi,India


Shashank R. JOSHI,MD, DM,
FACP (USA), FACE (USA), FRCP(Glsg)
Professor, Consultant Endocrinologist
Lilavati & Bhatia Hospital, Mumbai, INDIA

(email: shashank.sr@gmail.com)

Historically, the measurement of glucose has been the means of diagnosing type 2 diabetes. Glycated hemoglobin (HbA1c) has the following technical advantages when compared with glucose testing for this purpose:
_ Standardization and alignment to the Diabetes Control and Complications Trial (DCCT)/United Kingdom Prospective Diabetes Study (UKPDS); measurement of glucose is less well standardized
_ Better index of overall glycemic exposure and risk for longterm complications
_ Substantially less biologic variability
_ Substantially less preanalytic instability
_ No need for fasting or timed samples
_ Relatively unaffected by acute (eg, stress- or illness-related) perturbations in glucose levels
_ Currently used to guide management and adjust therapy

The screening tests to identify individuals at elevated risk for type 2 diabetes are the same as the diagnostic tests; therefore, the advantages of HbA1c testing compared with glucose testing apply to the screening for detection of individuals at high risk as well.

There are, however, limitations to the use of HbA1c for screening. In some parts of the world, the costs of providing for its assay preclude routine use. In addition, there are patient conditions, such as HbS, HbC, HbF, and HbE, that interfere with some HbA1c assay methods that either will require a specific HbA1c assay method or will preclude HbA1c testing. Any condition that changes red cell turnover, such as hemolytic anemia, chronic malaria, major blood loss, or blood transfusion, will lead to spurious HbA1c results. Clinicians must be aware of these conditions, particularly in populations in which they are more prevalent. HbA1c levels appear to increase with age, but the extent of the change, whether it relates to factors other than glucose metabolism, and the effect of the age-related increases on the development of complications are not sufficiently clear to adopt age-specific values in a screening scheme. Similarly, racial disparities in HbA1c, based on putative differences in the relationship between glucose levels and HbA1c, have been suggested; however, here too, their etiology and significance are unclear, and it is premature to establish race-specific diagnostic values. Finally, there are rare clinical settings, such as rapidly evolving type 2 diabetes, where the HbA1c level will not have had time to “catch up” with the acute elevations in glucose levels; however, in these very rare cases, diabetes should be diagnosable with typical symptoms and casual glucose levels >200 mg/dL (11.1 mmol/L), despite a nondiagnostic HbA1c level. The above section highlights the false positive and false negatives of HbA1c that are relevant to clinicians.

Based on a detailed review, an international Expert Committee1 has concluded that the best current evidence supports the following recommendations:
_ Individuals with an HbA1c level <6% but >6.5% are likely to be at the highest risk for progression to diabetes, but this range should not be considered an absolute threshold at which preventative measures are initiated.
_ The classification of subdiabetic hyperglycemia, such as prediabetes, is problematic because it suggests that all individuals so classified will develop diabetes and that individuals who do not meet these glycemia-driven criteria (regardless of other risk factor values) are unlikely to develop diabetes— neither of which is the case. Moreover, the categorical classification of individuals as high risk (eg, impaired fasting glycemia [IFG] or impaired glucose tolerance [IGT]) or low risk, based on any measure of glycemia, is less than ideal because the risk for progression to diabetes appears to be a continuum. Glucose-related terms describing subdiabetic hyperglycemia will be phased out of use as clinical diagnostic states, as HbA1c measurements replace glucose measurements for the diagnosis of diabetes.
_ When assessing risk, implementing prevention strategies, or initiating a population-based prevention program, other diabetes risk factors should be taken into account. In addition, the HbA1c level at which to begin preventive measures should reflect the resources available, the size of the population affected, and the anticipated degree of success of the intervention. Further analyses of cost-benefit should guide the selection of high-risk groups targeted for intervention within specific populations.
_ In developed economies where methodologies are well standardized, HbA1c may be used as a diagnostic add-on tool. But in developing countries where both liberal use as well as standardization of methodology is poor, it is a premature step. Also, there is still a role for glucose tolerance curves in modern metabolic medicine in several areas of epidemiology as well as clinical practice.
_

Reference
1. International Expert Committee. International expert committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care. 2009;32:1327-1334.

6.E. Mannucci,Italy


Edoardo MANNUCCI,MD
Agenzia Diabetologia
Padiglione Ponte Nuovo
Via delle Oblate, 4
50141 Firenze, ITALY

(e-mail: edoardo.mannucci@unifi.it)

An International Expert Committee, which included members designated by American, European, and International Diabetes Associations, proposed to include glycated hemoglobin (HbA1c) among the diagnostic criteria for diabetes, with a threshold of 6.5%.1 HbA1c is a more stable parameter than blood glucose,1,2 allowing a reliable assessment of carbohydrate metabolism without the need for repeated measurements that are required for the diagnosis of diabetes based on glycemic levels. The greater stability of this parameter may explain the results of epidemiological studies showing that HbA1c is a better predictor of the microvascular complications of diabetes and cardiovascular disease than either fasting glucose or postload/postprandial glucose.1-3 Furthermore, both fasting and postload glucose contribute to HbA1c .

Individual patients can show an isolated increase in postload glucose with normal fasting glycemia and vice-versa. Any screening strategy based on fasting glucose only will inevitably miss some diabetic patients with isolated postload hyperglycemia. The use of HbA1c can overcome this problem. A further advantage of HbA1c over blood glucose as a screening tool for diabetes is that it does not need to be measured in a fasting state—which can be difficult to ascertain.

On the other hand, the use of HbA1c as a screening and diagnostic tool has some disadvantages, which should be recognized. The correct measurement of this parameter requires high pressure liquid chromatography (HPLC) apparatus, which is not always available in peripheral laboratories. Values of HbA1c obtained with different methods can be very misleading. Furthermore, the standardization of HPLC methods is far from complete.4 The use of the so-called Diabetes Control and Complications Trial (DCCT)-aligned standards attenuates the problem without completely eliminating it; in fact, a certain interlaboratory variability persists even among DCCTaligned laboratories. It should also be considered that several conditions can lead to an increase or decrease in HbA1c levels independent of glucose metabolism; these include several forms of anemia, hemoglobinopathies, malaria, alcohol abuse, splenectomy, etc. Therefore, the results of measurements of HbA1c should always be carefully interpreted by clinicians. We should be aware that, particularly in older patients, the use of HbA1c could lead to an overestimation of the prevalence of diabetes. A further problem is the cost of determining HbA1c, which is higher than that for determining blood glucose; this aspect is a relevant limitation for HbA1c-based screening programs in underdeveloped countries, some of which have a high prevalence and incidence of diabetes.

Any clinical decision should be based on a careful evaluation of advantages and disadvantages. Although the standardization of laboratory procedures and costs are relevant issues, the benefits of using HbA1c in the screening of diabetes largely outweigh the disadvantages. In particular, the possibility of identifying cases of diabetes characterized by postload hyperglycemia with normal (or near-to-normal) fasting glucose, without the need to perform an oral glucose tolerance test is a major advantage, together with the possibility of diagnosing diabetes without the need to repeat the test, and of using blood samples drawn under nonfasting conditions for screening. At the same time, clinicians should be aware that values of HbA1c should not be used for diagnosis without critical consideration of the clinical conditions that could interfere with results. _

References
1. International Expert Committee. International expert committee report on the role of A1C assay in the diagnosis of diabetes. Diabetes Care. 2009;32:1327-1334.
2. Vistisen D, Colagiuri S, Borch-Johnsen K; DETECT-2 Collaboration. Bimodal distribution of glucose is not universally useful for diagnosing diabetes. Diabetes Care. 2009;32:397-403.
3. Khaw KT,Wareham N, Bingham S, Luben R,Welch A, Day N. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med. 2004;141:413- 420.
4. Consensus Committee. Consensus Statement on the worldwide standardization of the haemoglobin A1c measurement: American Diabetes Association, European Association for the Study of Diabetes, International Federation of Clinical Chemistry and Laboratory Medicine, and the International Diabetes Federation. Diabetes Care. 2007;30:2399-2400.

7.J. F. Raposo,Portugal


João F. RAPOSO,MD, PhD
Rua do Salitre, 118-120, 1250
203 Lisbon, PORTUGAL

(e-mail: filipe.raposo@sapo.pt)

Not yet. In contrast to type 1 diabetes, type 2 diabetes mellitus (T2DM) has been a difficult disease to diagnose throughout time. In fact, apart from their common definition as hyperglycemic conditions, their etiologies are significantly different.

But T2DMitself can be a heterogeneous disease, clinically varying from abnormal postprandial hyperglycemia to fasting hyperglycemia, or in some instances, both. Even from an investigational point of view, no consensus has been attained. In the last few decades, numerous techniques (clamps, glucose/ insulin ratios, mathematical models) have been presented that only reveal details of this regulation, and genetic research is still far from identifying a common factor (if there is one).

Considering these facts, the pertinent questions are why is it important to diagnose T2DM and why is earlier better? Here, we have consensus. We know that diabetes should be diagnosed to prevent micro- and macrovascular disease, causes of morbidity and mortality. We know now that our therapeutic armamentarium is capable of changing the natural history of T2DM. We also know that macrovascular disease starts during the early stages of this condition.

T2DM has a high prevalence. In Portugal, recent data point to 11.7% of the population (aged between 20 and 79 years) as having diabetes, 43% of whom are unaware of the diagnosis. The diagnosis in these cases was obtained via fasting hyperglycemia, an abnormal 2-hour oral glucose tolerance test (OGTT) value, or both. Are these good screening tools? Are they easy to use and inexpensive, with good specificity and sensitivity? For years, we have used OGTT as the gold standard for the diagnosis of T2DM. Because of the different costs involved with this test, we later evolved to using the fasting glycemia criterion, lowering the reference value from 7.77 mmol/L (140 mg/dL) to 7 mmol/L (126 mg/dL) to increase sensitivity. Several studies then demonstrated that while there is certainly a considerable overlap in the populations diagnosed by these two different criteria, there are still significant proportions diagnosed by each one. What does this mean? Probably that they detect the previously referred to T2DM heterogeneity.

In 2009, the American Diabetes Association (ADA) adopted a new criterion. Representing a “physiological” average of glycemic fluctuations, glycated hemoglobin (HbA1c) is certainly a tempting candidate for a good screening tool. What has to be demonstrated before its acceptance for widespread use?
We have to consider methodological arguments: there is still no international consensus in the use of standards or units for HbA1c, and regional differences in the normal distribution of HbA1c are not known.

The cost of an HbA1c test is significantly higher than the cost of measuring glycemia. The recent appearance of point-of-care HbA1c determination using different methodologies (and different correlations to the high pressure liquid chroma
tography [HPLC] standard) has created more interest in this new diabetes diagnostic criterion.

Apart from the methodological questions, there are others still waiting to be answered: Is the choice of an HbA1c value of 6.5% the best one for all? What is the overlap of T2DM diagnosis using HbA1c with the previously used criteria? Which populations (if there are any) are at greater risk of developing complications: a population with fasting hyperglycemia, with postprandial hyperglycemia, or with elevated HbA1c? Is glycemic variability, considered by some to be an indicator of increased cardiovascular risk, expressed by HbA1c?

In my opinion, and having discussed all these arguments, I consider the ADA’s current recommendation of continuing to use previous criteria and of using the new HbA1c one for the diagnosis of diabetes to be at least prudent and will give us time to answer all these questions. After decades of apparent stagnation, diabetes has been in a state of constant turmoil in the last few years, in different fields. A period of judicious reflection should follow. _

8.O. M. Smirnova,Russia


Olga M. SMIRNOVA,MD, PhD, DMedSc
Federal State Institution: Endocrinology
Research Center under the Federal Agency
for High-Tech Medical Care
11 Dmitriya Ulyanova str
Moscow 117036, RUSSIA

(e-mail: dr_smr@mail.ru)

Over the past few decades, the diagnosis of diabetes mellitus (DM) has been based on plasma glucose levels, either fasting or 2 hours after a 75-gram oral glucose load. While developing the new diagnostic criteria in 1997, the first Expert Committee on the Diagnosis and Classification of Diabetes Mellitus considered the results of studies that examined the association between fasting plasma glucose (FPG) levels and retinopathy development. Three epidemiologic studies identified the glycemic level below which there was minimal prevalence of retinopathy and above which the prevalence of retinopathy increased in a linear progression. The values of FPG, 2-hour plasma glucose after a 75- gram oral glucose load, and glycated hemoglobin (HbA1c) were the same for each population. Their study findings allowed the establishment of the diagnostic criteria that are currently recommended by the World Health Organization (WHO).

There are many cases of diabetes that are still not diagnosed in a timely manner. The need for active screening and early detection of DM is highlighted by the fact that about half of patients already have at least one diabetes-related complication at the time of diagnosis.

In January 2010, the American Diabetes Association (ADA) first recommended the use of an HbA1c test to diagnose diabetes, with a threshold of ≥6.5% for identifying diabetes, and a range of 5.7% to 6.4% for prediabetes screening. Before this date, the International Expert Committee, after a review of epidemiological studies, had already proposed using an HbA1c test for diagnosing diabetes, but this suggestion had been rejected, partly due to the absence of standardization of the assay. Today, HbA1c assays are highly standardized, therefore their results can be uniformly applied.

The diagnostic test should be performed using a method certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized in accordance with the Diabetes Control and Complications Trial (DCCT) reference assay. The measurement of HbA1c as the diagnostic criterion of diabetes has some advantages, since it is more convenient (as fasting is not required), more stable, less variable, and less affected by temporal factors, such as stress and coexisting diseases.

The relationship between HbA1c values andmean glucose levels has been unequivocally established. However, it should be remembered that HbA1c level as an indicator of glycemic control has several limitations, as it can increase in nondiabetic patients with end-stage renal failure receiving hemodialysis treatment, in patients with iron deficiency anemia, dyslipidemia, or cirrhosis, as well as in pregnant women. The diagnostic value of HbA1c can be limited in conditions associated with decreased erythrocyte lifetime (eg, in hemolytic anemia) or in hemoglobinopathies. This should be kept in mind in cases where the results of HbA1c do not correspond to the clinical situation in a particular patient.

The new ADA recommendation to use HbA1c assays for the screening of diabetes and prediabetes is an important step forward in the diagnosis of the disease. Indeed, the determination of HbA1c should be considered more objective and reliable than that of FPG and even that of the oral glucose tolerance test (OGTT), as HbA1c reflects the state of carbohydrate metabolism over a long-term period. Random plasma glucose measurement requires confirmation with an additional OGTT examination. Moreover, HbA1c measurement does not require any special preparation or additional time, whereas the OGTT and simple FPG test require a carbohydrate diet in the days preceding the test, starvation before the test, as well as prolonged examination time.

I suppose the HbA1c test would be preferable for screening in high-risk populations. However, to verify the diagnosis of DM in asymptomatic patients, as well as prediabetes in the case of elevated HbA1c, it will also be necessary to repeat this test or perform an OGTT.

The significant arguments against the routine use of this assay for these purposes in our country today are the higher cost of the analysis and the absence of the corresponding standardized methods and equipment. I suppose that another obstacle is doctors’ inertia of thinking, especially general practitioners and physicians. On the other hand, in large medical centers, it is not only possible, but entirely feasible to use this assay for screening the limited number of subjects at high risk of DM with obesity and vascular diseases._

9.B. L. Wajchenberg,Brazil


Bernardo L. WAJCHENBERG,MD, PhD
University of São Paulo Medical School
São Paulo, SP, BRAZIL

(e-mail: bernarwaj@gmail.com)

According to what has been suggested by experts in the area of diabetes and now by the American Diabetes Association (ADA), which considers glycated hemoglobin (HbA1c) an appropriate diagnostic test, the main factors in support of using HbA1c as a screening and diagnostic test are: HbA1c does not require patients to fast; it is a marker of chronic glycemia, reflecting average plasma glucose levels over 2 to 3 months; less day-to-day perturbations during periods of stress and illness; methods for its measurement are standardized and reliable; and errors caused by nonglycemic factors, such as hemoglobinopathies, are infrequent. The cutoff point suggested was 6.5%, as at this level the prevalence of diabetic retinopathy begins to rise above that of nondiabetic patients.

A disadvantage of the measurement of HbA1c for screening and diagnosis of diabetes is an incomplete correlation between HbA1c and average plasma glucose in “high glycators,” who have a higher HbA1c than that predicted with actual mean glucose level, while “low glycators” exhibit opposite characteristics. A quarter of the population exhibits one or other extreme glycator profiles, so the use of HbA1c levels as absolute “goals” for diagnosis and treatment is “inappropriate if not coupled with glucose measurements.”1

The existing glycemic criteria for diagnosing diabetes—fasting plasma glucose (FPG) ≥126 mg/dL, and random plasma glucose or 2-h post–oral glucose tolerance test (OGTT) plasma glucose ≥200 mg/dL—which were originally established based on an expert committee’s evaluation of levels of glycemia associated with diabetic retinopathy, continue to be accepted as criteria for the diagnosis of diabetes. Since, as indicated, the concordance between HbA1c and glucose-based tests is not complete, particularly considering that HbA1c, FPG, and 2-h post-OGTT measure different physiological processes, it has been suggested that an HbA1c from 6.5% to 6.9% or higher, be considered a screening test requiring confirmation by the diagnosis of diabetes using direct measures of glucose.

In the Hoorn study in 2753 subjects aged 45 to 65 years, the correlations between HbA1c and FPG and 2-h post-OGTT glucose were 0.45 and 0.33, respectively, so that no more than one-quarter of the variance in HbA1c could be explained by glycemia. In this study, HbA1c >6.5% was quite specific. Its sensitivity being low, the current OGTT criteria failed to identify a high proportion of individuals with HbA1c >6.5%.2 Similar findings were observed in other studies.

Regarding the high-risk categories of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), it was suggested that an HbA1c of 6.0% to 6.4% would identify patients at high risk for diabetes (ie, progressing to >6.5%), so in a sense, these patients would represent a group equivalent to those classified as having IFG/IGT. However, this does not imply that populations at lower HbA1c levels are not at risk but, rather, they are at lower risk, since the risk for diabetes appears to be a continuum.3 It can be argued that is also the case with HbA1c, and any cutoff values chosen are somewhat arbitrary.

Using two cutoff values, rather than one, for HbA1c gives high sensitivity for screening plus optimal specificity for diabetes diagnosis: HbA1c ≤5.5% and ≥7.0% predicts the absence and presence of type 2 diabetes, while with an HbA1c of 6.5%- 6.9%, diabetes is highly probable.4 _

References
1. Bloomgarden ZT, Einhorn D. Hemoglobin A1c in diabetes diagnosis: Time for caution. Endocr Pract. 2010;16:5-6.
2. van’t Riet E, Alssema M, Rijkelijkhuizen JM, Kostense PJ, Nijpels G, Dekker JM. Relationship between A1c and glucose levels in the general Dutch population: The new Hoorn Study. Diabetes Care. 2010;33:61-66.
3. International Expert Committee: International expert committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care. 2009;32:1-8.
4. Lu ZX, Walker KZ, O’Dea K, Sikaris KA, Shaw JE. A1c for screening and diagnosis of type 2 diabetes in routine clinical practice. Diabetes Care. 2010;33: 817-819.