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Screening for diabetes: is it warranted?
Clinica Chimica Acta 315 Ž2002. 61–69 www.elsevier.comrlocaterclinchim
Review article
Screening for diabetes: is it warranted? Roger A. Greenberg, David B. Sacks ) Department of Pathology, Brigham and Women’s Hospital and HarÕard Medical School, Boston, MA 02115 USA Received 4 May 2001; accepted 6 July 2001
Abstract Background: Diabetes mellitus is estimated to have a worldwide prevalence of 4.6% and afflict 200 million people. The prevalence is accelerating rapidly and the disease has reached epidemic proportions. While type 1 diabetes usually has a dramatic clinical onset, almost half of all those individuals with type 2 diabetes have not been diagnosed. This observation, coupled with the presence of complications at diagnosis and the significant reduction of microvascular complications obtained with tight glycemic control, has led to the recommendation that screening for diabetes be instituted. The American Diabetes Association recommends that adults aged 45 years or more should be evaluated for diabetes by measuring fasting plasma glucose concentrations. Conclusions: The rationale for screening, evidence that tight glycemic control reduces complications, and the possible roles of Hb A 1c and autoantibodies in screening strategies are addressed in this review. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Diabetes; Screening; Glycohemoglobin; Hb A 1c
1. Significance of diabetes mellitus 1.1. Introduction Diabetes mellitus is a group of metabolic disorders with different underlying etiologies, each characterized by hyperglycemia due to underuti-
AbbreÕiations: OGTT, oral glucose tolerant test; IGT, impaired glucose tolerance; IFG, impaired fasting glucose; FPG, fasting plasma glucose; BMI, body mass index; DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study; ADA, American Diabetes Association. ) Corresponding author. Department of Pathology, Brigham and Women’s Hospital, Thorn 530, 75 Francis Street, Boston, MA 02115 USA. Tel.: q1-617-732-6627; fax: q1-617-278-6921. E-mail address: [email protected] ŽD.B. Sacks..
lization of glucose. The disease is classified into several major groups. Type 1 diabetes mellitus, formerly known as insulin-dependent diabetes mellitus ŽIDDM. or juvenile onset diabetes mellitus, is caused by autoimmune destruction of the b-cells of the pancreas, rendering the pancreas unable to synthesize and secrete insulin w1x. Type 2 diabetes mellitus, formerly known as non-insulin-dependent diabetes mellitus ŽNIDDM. or adult-onset diabetes, results from a combination of insulin resistance and inadequate secretion of insulin w2,3x. Type 2 is the most common form, accounting for 90–95% of diabetes in developed countries. A third category, termed gestational diabetes, is the development of glucose intolerance during pregnancy w4x. Screening high-risk individuals for gestational diabetes during prenatal care has been strongly advocated for several years w4x and will not be discussed further in this review.
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Screening of asymptomatic individuals for type 2 diabetes has been the subject of much controversy. The American Diabetes Association ŽADA., which previously did not support screening w5x, revised their recommendations in 1997 to favor screening w6x. What is the rationale underlying this support for screening? Because it is frequently asymptomatic, 33%–50% of those individuals with type 2 diabetes have not been diagnosed w7x. Moreover, because the onset of the disease is believed to occur 4–7 years before diagnosis, many patients with type 2 diabetes have complications of the disease by the time of clinical diagnosis w8x. The third reason is that early diagnosis and therapeutic intervention is thought to prevent or delay the onset of complications. The excellent outcomes data that clearly document the benefits of good metabolic control in individuals with the disease w9x have led to the inference that screening programs for type 2 diabetes mellitus should be instituted. This assertion, however, is not supported by any controlled study and thus a recommendation for population screening for diabetes mellitus is not an evidence-based strategy. This review will describe the significance of diabetes and examine the rationale that led to the advocation of screening for diabetes.
world is predicted to be substantially greater than the 42% rise in the developed world w12x. Therefore, by the year 2025, ) 75% of individuals with diabetes will live in developing countries. Much of this predicted gain is related to a dramatic rise in obesity. There is a large body of data linking obesity to the development of type 2 diabetes w13x. Virtually all obese individuals are insulin resistant and 60%–80% of patients with type 2 diabetes are obese. Prospective studies—such as the Nurses Cohort Study—have established that Žafter adjusting for age. body mass index ŽBMI. is the primary predictor for the development of diabetes w14x. An additional independent risk factor for diabetes is the distribution of fat. After controlling for BMI, a waist circumference ) 40 in. Ž102 cm. increases the risk of diabetes by 3.5-fold w15x. Although only 15% of obese individuals develop diabetes, the rapidly increasing prevalence of obesity in both the developed and developing world w13x makes it likely that diabetes mellitus will continue to have a major impact on world healthcare ŽFig. 1.. For example, the prevalence of obesity ŽBMI G 30 kgrm2 . in the U.S. increased from 12.0% in 1991 to 17.9% in 1998 w16x.
1.2. Epidemiology of diabetes mellitus
Individuals with diabetes are at significantly increased risk for the development of debilitating complications w17x. These are microvascular—predominantly retinopathy, nephropathy and neuropathy— and macrovascular, particularly stroke and coronary artery disease, the last resulting in acute myocardial infarction. Furthermore, acute episodes such as diabetic ketoacidosis, hyperosmolar coma, and severe hypoglycemia contribute to the morbidity and mortality of the disease. It is thus not surprising that diabetes is currently the seventh most common cause of death in the developed world w18x. This figure is likely to be an underestimate given the total number of undiagnosed cases of diabetes and the low specificity for diabetes-related causes of death, such as cerebrovascular accident and myocardial infarction. In addition to being a major cause of mortality, diabetes is the most common cause of limb amputations and end-stage renal disease w19x. After 20 years of diabetes, virtually all patients with type 1 diabetes and ) 60% of type 2 diabetes have retinopathy,
A global epidemic of diabetes is predicted for the first quarter of the 21st century. In the U.S. in 1998 approximately 6.5% of the population Žover 16 million people. were diagnosed with type 2 diabetes and a roughly equivalent number were estimated to be undiagnosed w10x. Addition of those undiagnosed yields a true prevalence in the US of ; 25 million. The prevalence is accelerating dramatically. Recent evidence reveals that the prevalence of diabetes in the US increased by 33% from 1990 to 1998 w10x, with a further 6% increase over the following year w11x. These statistics are not confined to the U.S. The worldwide prevalence of diabetes in persons G 20 years was 4.0% in 1995 and is expected to reach 5.4% Žover 300 million people. by 2025 w12x. The percentage of diabetics in 2025 in the developed world is anticipated to reach 7.6%. Although the comparable figure in the developing world is lower at 4.9%, the 170% rate of increase in the developing
1.3. Complications
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as a result of the increased prevalence of other general medical conditions seen in diabetic patients w20x. The indirect costs comprised US$17 billion for the estimated 150,000 annual deaths and US$37 billion from disability. The annual per capita health care costs for an individual with diabetes are approximately fourfold higher than those for a person who does not have diabetes w20x. Similarly, in the UK diabetes accounts for roughly 10% of the National Health Service budget Ž£49 billion.. Effective therapies to ameliorate the complications of diabetes could thus lessen the economic impact of diabetes. However, many patients have complications at the time of diagnosis of type 2 diabetes w8x. Therefore, the full impact of therapy to reduce the medical expenditure on diabetes will not be realized until the majority of patients likely to benefit from treatment are successfully identified and given appropriate medical care.
2. Tight glycemic control reduces the morbidity of diabetes
Fig. 1. Relation between BMI up to 30 and the relative risk of type 2 diabetes, hypertension, CHD and cholelithiasis. Ža. Relations for women, initially 30 to 55 years old, who were followed up to 18 years. Žb. Relations for men, initially 40–65 years old, who were followed up to 10 years w13x.
rendering diabetic retinopathy the most frequent cause of blindness in adults. Together these factors result in health care expenditures for diabetes far exceeding the prevalence of the disease in the general population. 1.4. Economic impact The costs of diabetes in the U.S. in 1992 were estimated to be US$98 billion w20x. This figure includes direct medical expenditures of US$44.1 billion and indirect costs of US$54.1 billion. The direct costs comprised US$7.7 billion for diabetes and acute glycemic care, US$11.8 billion attributed to diabetes-related complications, and US$24.6 billion
For many years it was hypothesized that the complications of diabetes were due to hyperglycemia. However, this assertion lacked convincing evidence until the last decade. Two large, randomised, well-designed multicenter trials clearly documented that improved glycemic control decreased the development of microvascular complications in individuals with type 1 w21x and type 2 diabetes w9x. These trials provide strong evidence that, regardless of the etiology, the microvascular complications of diabetes mellitus are due to hyperglycemia. The first major study to demonstrate this finding was the Diabetes Control and Complications Trial ŽDCCT., which revealed in a landmark publication in 1993 that strict glycemic control in patients with type 1 diabetes significantly diminished the incidence and progression of microvascular complications w21x. The DCCT study contained 1441 individuals who were randomly assigned to intensive glucose-lowering therapy or conventional therapy with insulin. The study period averaged 7 years. The goals of intensive therapy were evaluated by self-monitoring of blood glucose ŽSMBG. four times a day and monthly
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measurement of Hb A 1c . Median Hb A 1c concentrations were 9.1% and 7.2% for the conventional and intensive therapy groups, respectively, for a 20% overall reduction in Hb A 1c concentrations. There was a direct relationship between the Hb A 1c concentration and the prevalence of microvascular complications. Patients in the intensively treated group had a significantly lower rate of microvascular complications. Compared to the conventionally treated group, the rates of retinopathy, nephropathy and neuropathy were reduced in the intensively treated group by 76%, 39% and 60%, respectively. Although the rate of macrovascular complications was reduced slightly by intensive therapy, this decrease was not statistically significant. What about type 2 diabetes? The United Kingdom Prospective Diabetes Study ŽUKPDS. w9x was a multicenter trial to determine the impact of intensive blood glucose control in subjects with type 2 diabetes. The study enrolled 5102 patients with newly diagnosed type 2 diabetes and blood glucose concentrations were controlled with oral agents andror insulin. Although the median Hb A 1c concentration in the intensively treated group was only 13% lower than in the conventional treatment group Ž7.0% and 7.9%, respectively., the prevalence of microvascular complications was reduced by 25% w9x. Despite the demonstrated efficacy in reducing hyperglycemia, no significant decrease in macrovascular complications or diabetes-related mortality was observed in the intensively treated group in the UKPDS w9x. Addi-
tionally, intensive treatment with insulin or sulfonylureas significantly increased the number of hypoglycemic episodes. Analogous to the DCCT, the UKPDS documented the value of glycohemoglobin analysis. There was a steep increase in the risk of complications for each 1% increase in Hb A 1c concentration. Conversely, decreasing Hb A 1c by 1% reduced microvascular complications by 35% and diabetes-related mortality by 25% w9x. Together these outcomes trials clearly demonstrate the value of Hb A 1c as an integral component of the management of diabetes and its ability to predict the development of complications. Based on these studies the ADA has identified clearly defined Hb A 1c target values for glycemic control w22x. These are: normal, - 6%; treatment goal, - 7% and modify therapy if Hb A 1c ) 8%.
3. Laboratory methods for the diagnosis of diabetes mellitus The diagnosis of diabetes is established exclusively by the demonstration of increased concentrations of glucose in the blood. For many years, the oral glucose tolerance test ŽOGTT. was the sole diagnostic criterion; the cutoff was 2 SD Žstandard deviations. above the mean of the glucose concentration in healthy volunteers. In 1979 revised criteria were proposed, including fasting plasma glucose ŽFPG. G 7.8 mmolrl Ž140 mgrdl. and a 2-h post-
Table 1 Criteria for the diagnosis of diabetes mellitusa IFG
IGT
Diabetesb
(A) ADA criteria FPG G 6.1 Ž110. and - 7.0 Ž126.
2-h PG G 7.8 Ž140. and - 11.1 Ž200.
FPG G 7.0 Ž126. or 2-h PG G 11.1 Ž200. or symptoms of diabetes and casual plasma glucose concentration G 11.1 Ž200.
(B) WHO criteria FPG G 6.1 Ž110. and - 7.0 Ž126. and 2-h PG - 7.8 Ž- 140. Žif measured.
FPG - 7.0 Ž126. Žif measured. and 2-h PG G 7.8 Ž140. and - 11.1 Ž200.
FPG G 7.0 Ž126. or 2-h PG G 11.1 Ž200. or both
See text for explanation. FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; 2-h PG, 2-h postload glucose. Adapted from Refs. w6,23x. a Glucose concentrations are in mmolrl Žmgrdl.. b If one of these criteria is met, diagnosis of diabetes must be confirmed by repeat testing on a subsequent day. The FPG test is preferred due to ease of administration.
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load glucose value G 11.1 mmolrl Ž200 mgrdl. w5x. Because the fasting and 2-h values were not equivalent, the criteria were modified in 1997 w6x. Based on a correlation between blood glucose concentrations and the risk of subsequent complications, the cutoff was lowered to FPG G 7.0 mmolrl Ž126 mgrdl. ŽTable 1.. Although the OGTT remained a diagnostic criterion, its use was discouraged w6x. Similarly, the World Health Organization ŽWHO. revised their diagnostic criteria ŽTable 1. w23x. Although some similarities to the ADA criteria are observed, the WHO continue to recommend the OGTT, albeit in an abbreviated form Žglucose need be measured only in a fasting sample and 2 h after a 75-g oral glucose load Žsee Ref. w23x for details..
4. Screening The ADA recommends screening for diabetes in all asymptomatic individuals over the age of 45 years by measurement of FPG w24x. If FPG is below 6.1 mmolrl Ž110 mgrdl., repeat testing is recommended at 3-year intervals. For individuals with defined risk factors for diabetes, including family history or obesity Žsee Table 2 for complete list., screening prior to the age of 45 years is recommended. Table 2 Criteria for testing for diabetes in asymptomatic, undiagnosed individuals Ž1. Testing for diabetes should be considered in all individuals at age 45 years and above and, if normal, it should be repeated at 3-year intervals. Ž2. Testing should be considered at a younger age or be carried out more frequently in individuals who: Ža. are obese Ž G120% desirable body weight or a BMIG127 kgrm2 . Žb. have a first-degree relative with diabetes Žc. are members of a high-risk ethnic population Že.g., African American, Hispanic American, Native American, Asian American, Pacific Islander. Žd. have delivered a baby weighing G9 lb. or have been diagnosed with GDM Že. are hypertensive ŽBPG140r90 mm Hg. Žf. have HDL cholesterol G 35 mgrdl Ž0.90 mmolrl. andror a triglyceride G 250 mgrdl Ž2.82 mmolrl. Žg. on previous testing, had IGT or IFG Adapted from Ref. w24x.
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4.1. Screening for type 2 diabetes 4.1.1. Fasting plasma glucose Measurement of FPG requires an overnight fast of G 8 h, during which time water, but not food, may be consumed. Glucose concentrations decrease ex vivo by approximately 5–7%rh due to glycolysis w25x. Unless the venous blood is subjected to centrifugation within 60 min to remove the cells, additives such as sodium fluoride or lithium iodoacetate should be included in blood collection tubes to inhibit glycolysis w25x. Plasma glucose is accurately measured by enzymatic assays. The vast majority of analyses in the U.S. use methods employing hexokinase or glucose oxidase w26x. Both methods have low imprecision, with intra-assay CVs Žcoefficients of variability. of - 4% at a plasma glucose concentration of ; 8.2 mmolrl Ž147 mgrdl.. Comparison of the two assays in 240 subjects yielded mean glucose concentrations of 101.6 " 4 and 96.7 q " 3.9 mgrdl for hexokinase and glucokinase, respectively, with an inter-assay difference of approximately 5% w27x. Glucose concentrations in whole blood can be rapidly measured with meters that are used by patients for self-monitoring, in hospitals at the patient’s bedside or in clinics and physician’s offices w26x. However, due to their large imprecision, these meters should not be used for screening or diagnosis. Although plasma glucose assays in the central laboratory have low imprecision, the biological variability for glucose is large. For example, consecutive determinations of FPG revealed an intra-individual CV of 7% in 246 non-diabetic patients w28x. Applying this biologic variability to a true glucose value of 7.0 mmolrl Ž126 mgrdl. would produce 95% CI Žconfidence intervals. of 6.0–8.0 mmolrl Ž108–144 mgrdl.. An additional factor that makes a significant contribution to variability is the diurnal fluctuation in FPG concentrations. This was demonstrated by evaluating 12,882 participants in the Third National Health and Nutrition Examination Survey ŽNHANES III. aged 20 years or older who had no previously diagnosed diabetes w29x. Subjects were randomly assigned to morning or afternoon FPG determinations. Mean FPG concentrations were significantly higher in the morning group w5.41 mmolrl Ž97.4 mgrdl.x
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than in the afternoon group w5.12 mmolrl Ž92.4 mgrdl.x. These differences resulted in a prevalence of diabetes wFPG G 7.0 mmolrl Ž126 mgrdlx in the afternoon group half of that for the morning group w29x. To obtain the same prevalence of diabetes as the morning-examined participants, a cutoff for FPG of 6.3 mmolrl Ž114 mgrdl. was required for the afternoon group. These results have major implications for diabetes screening, as many patients are seen by their physicians in the afternoon and approximately half of all cases of undiagnosed diabetes in these patients will be missed. Therefore, we recommend that screening for type 2 diabetes be performed in the morning whenever feasible.
4.1.2. The oral glucose tolerance test Previously the OGTT was the primary means of diagnosing diabetes. The ADA no longer recommends its use in non-pregnant individuals, but an abbreviated version forms an important component of WHO recommendations w23x. The protocol for performing an OGTT requires an overnight fast of 8–14 h. After obtaining a fasting blood sample, the patient receives 75 g of glucose orally and blood is sampled 2 h later. Plasma glucose concentrations G 11.1 mmolrl Ž200 mgrdl. in the 2-h sample are diagnostic of diabetes. The WHO recommends that the OGTT be used when FPG is in the impaired fasting glucose ŽIFG. range of 6.1–6.9 mmolrl Ž110–125 mgrdl.. The ADA advocates elimination of the OGTT because it has poor reproducibility, is time-consuming and expensive, requires extensive patient preparation, lacks standardization of the glucose load and requires multiple venipuncture w30x. The poor reproducibility is exemplified by a study of 524 subjects without a history of diabetes who were evaluated with two OGTTs performed 2 to 6 weeks apart w31x. Of the 198 patients classified with impaired glucose tolerance ŽIGT. by the first OGTT, 78 Ž39%. and 25 Ž13%. were classified with normal glucose tolerance and diabetes, respectively, by the second OGTT. If the initial OGTT is used as the gold standard, repetition of the OGTT will misclassify half of the subjects close to the cutoff. However, the OGTT is more sensitive than FPG because impaired release of insulin in response to glucose develops earlier in the
course of type 2 diabetes than increased fasting glucose. Therefore, screening for diabetes by the OGTT yields a prevalence of diabetes higher than that obtained by FPG. For example, Harris et al. w32x detected a prevalence of undiagnosed diabetes in NHANES III of 6.4% and 4.4% by WHO and ADA criteria, respectively. However, individuals classified by ADA criteria were observed to be more hyperglycemic and had higher Hb A 1c concentrations w32x. Therefore, use of the OGTT remains contentious. 4.1.3. Hb A 1c All proteins undergo non-enzymatic glycation. Addition of glucose to hemoglobin results in the formation of glycohemoglobin. A component of glycohemoglobin, Hb A 1c , is formed by the addition of glucose to the N-terminal valine residue of the bchain of hemoglobin A ŽHbA.. Because the average lifespan of an erythrocyte is 120 days, the Hb A 1c concentration—expressed as the percentage of total hemoglobin—reflects the mean glucose concentration over the preceding 6 to 8 weeks w26x. What is the rationale for screening for diabetes with Hb A 1c? Because it reflects the integrated glucose concentration over time, Hb A 1c is not subject to the wide diurnal fluctuations seen with blood glucose concentrations. Patients do not need to be fasting at the time of blood sampling and the intraindividual variability is low. Perhaps most importantly, the Hb A 1c value correlates directly with microvascular complications and predicts their development. Together these factors mitigate for the use of Hb A 1c for screening of asymptomatic individuals for diabetes. It has been argued that the large imprecision and lack of standardization of Hb A 1c assays precludes its use as a screening modality. The significant role of Hb A 1c in the DCCT led to the establishment of the National Glycohemoglobin Standardization Program ŽNGSP. in 1996. The goal of the NGSP is to standardize Hb A 1c assays to DCCT-equivalent values. Working closely with manufacturers of instruments for Hb A 1c analysis and monitoring progress with proficiency material from the College of American Pathologists ŽCAP., the NGSP has made substantial progress towards attaining this goal Ždetailed information is available at the NGSP website: http:rrwww.missouri.edur; diabetesrngsp.html...
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This progress suggests that Hb A 1c may be useful for screening and this thesis is supported by preliminary studies. For example, David Goldstein’s group screened 6559 participants in NHANES III by FPG and Hb A 1c . Diabetes was diagnosed if FPG G 7.0 mmolrl. Selecting a cutoff for Hb A 1c of 5.6% Ž1 SD above the normal mean. yielded a sensitivity of 83.4% and specificity of 84.4% for the diagnosis of diabetes w33x. If a cutoff of 6.1% Ž2 SD above the normal mean. was used, sensitivity and specificity were 63.2% and 97.4%, respectively. An alternative strategy using a two-step procedure for screening has been proposed by Davidson et al. w34x: individuals with FPG of 6.1–7.7 mmolrl Ž110– 139 mgrdl. should be followed with analysis of Hb A 1c . Diabetes would be diagnosed only if the Hb A 1c value on two separate occasions was 1% above the upper limit of the reference interval for the assay used. The rationale underlying this proposal is that a large percentage of individuals with FPG values ) 7.0 mmolrl Ž126 mgrdl. do not have evidence of long-term hyperglycemia by Hb A 1c analysis w34x. A limitation of Hb A 1c analysis is possible interference in the assay. Hemoglobin variants—such as HbS, HbC and HbE—and chemically modified derivatives, such as carbamyl-hemoglobin, may yield spurious results when Hb A 1c is measured w35x. Moreover, any condition that alters erythrocyte halflife, including hemolysis, hemorrhage or transfusion, result in Hb A 1c values that do not reflect long-term glycemia w35x. It would not be possible to use Hb A 1c for screening or diagnosis in patients with these conditions.
4.4. Screening for type 1 diabetes Is there a role for screening for type 1 diabetes? Although the prevalence is much lower than that of type 2 diabetes, the type 1 form of the disease is also becoming more common. The global incidence of type 1 diabetes is increasing by approximately 3% per year w36x. Moreover, ; 10% of individuals classified with type 2 diabetes have islet autoantibody markers of type 1 diabetes w37,38x. These patients with possible slow-onset type 1 diabetes are usually
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not adequately controlled with oral hypoglycemic agents and require insulin therapy for good metabolic control. Type 1 diabetes is an autoimmune disease. Autoantibodies are produced to several islet autoantigens, including insulin, the 65-kDa glutamic acid decarboxylase isoform ŽGAD65. and the protein tyrosine phosphatase IA-2 w39x. The simultaneous detection in the blood of all three autoantibodies in first-degree relatives of individuals with type 1 diabetes is highly predictive of the development of the disease w40,41x. However, no therapeutic intervention has been identified that will prevent or significantly delay the onset of the disease. Moreover, unlike type 2 diabetes which is frequently clinically silent, type 1 diabetes usually exhibits a dramatic clinical onset. Therefore, there is no current role for general population screening for type 1 diabetes by autoantibody testing. Moreover, the ADA does not recommend screening for unaffected first-degree relatives of individuals with type 1 diabetes because of the lack of evidence as to how to proceed after a positive test w24x. Islet autoantibody screening of first-degree relatives is currently used in clinical trials, several of which are underway. Large studies of diabetes prevention, such as the Diabetes Prevention Trial Type-1 ŽDPT-1. w42x, are likely to reveal whether the onset of type 1 diabetes can be delayed by the institution of therapy prior to the onset of clinical symptoms.
5. Conclusions Screening for diabetes is a highly contentious topic. In the absence of data to support widespread population screening, a somewhat intuitive approach has been taken by the ADA in its recommendations w24x. Laboratory medicine has made an essential contribution to the success of diabetes screening. Clinical laboratories have facilitated marked improvements in glucose assays, substantially reducing the imprecision. Currently, considerable effort is directed towards Hb A 1c standardization. In addition to the NGSP, the International Federation for Clinical Chemistry ŽIFCC. has joined the standardization effort and two candidate reference methods for Hb A 1c have been developed w43x. Initial comparisons appear
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to indicate a linear relationship between the IFCC and NGSP Laboratory Networks. These advances augur well. We eagerly await long-term outcomes studies to provide an evidence-based approach to finally resolve the question of whether to institute widespread population screening for diabetes.
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recombinant human islet glutamic acid decarboxylase ŽGAD65. shows that 64 K autoantibody positivity at onset predicts diabetes type. J Clin Invest 1993;91:368–74. Schranz DB, Lernmark A. Immunology in diabetes: an update. Diabetes Metab Rev 1998;14:3–29. Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, et al. Prediction of type I diabetes in first-degree relatives using a combination of insulin GAD, and ICA512bdcrIA-2 autoantibodies. Diabetes 1996;45:926–33. Bingley PJ, Bonifacio E, Ziegler AG, Schatz DA, Atkinson MA, Eisenbarth GS. Proposed guidelines on screening for risk of type 1 diabetes. Immunology of Diabetes Society. Diabetes Care 2001;24:398. Group D-S. The Diabetes Prevention Trial Type 1 diabetes ŽDPT-1.: implementation of screening and staging of relatives. Transplant Proc 1995;27:3377. Kobold U, Jeppsson JO, Dulffer T, Finke A, Hoelzel W, Miedema K. Candidate reference methods for hemoglobin A1c based on peptide mapping. Clin Chem 1997;43:1944–51.
Review article
Screening for diabetes: is it warranted? Roger A. Greenberg, David B. Sacks ) Department of Pathology, Brigham and Women’s Hospital and HarÕard Medical School, Boston, MA 02115 USA Received 4 May 2001; accepted 6 July 2001
Abstract Background: Diabetes mellitus is estimated to have a worldwide prevalence of 4.6% and afflict 200 million people. The prevalence is accelerating rapidly and the disease has reached epidemic proportions. While type 1 diabetes usually has a dramatic clinical onset, almost half of all those individuals with type 2 diabetes have not been diagnosed. This observation, coupled with the presence of complications at diagnosis and the significant reduction of microvascular complications obtained with tight glycemic control, has led to the recommendation that screening for diabetes be instituted. The American Diabetes Association recommends that adults aged 45 years or more should be evaluated for diabetes by measuring fasting plasma glucose concentrations. Conclusions: The rationale for screening, evidence that tight glycemic control reduces complications, and the possible roles of Hb A 1c and autoantibodies in screening strategies are addressed in this review. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Diabetes; Screening; Glycohemoglobin; Hb A 1c
1. Significance of diabetes mellitus 1.1. Introduction Diabetes mellitus is a group of metabolic disorders with different underlying etiologies, each characterized by hyperglycemia due to underuti-
AbbreÕiations: OGTT, oral glucose tolerant test; IGT, impaired glucose tolerance; IFG, impaired fasting glucose; FPG, fasting plasma glucose; BMI, body mass index; DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study; ADA, American Diabetes Association. ) Corresponding author. Department of Pathology, Brigham and Women’s Hospital, Thorn 530, 75 Francis Street, Boston, MA 02115 USA. Tel.: q1-617-732-6627; fax: q1-617-278-6921. E-mail address: [email protected] ŽD.B. Sacks..
lization of glucose. The disease is classified into several major groups. Type 1 diabetes mellitus, formerly known as insulin-dependent diabetes mellitus ŽIDDM. or juvenile onset diabetes mellitus, is caused by autoimmune destruction of the b-cells of the pancreas, rendering the pancreas unable to synthesize and secrete insulin w1x. Type 2 diabetes mellitus, formerly known as non-insulin-dependent diabetes mellitus ŽNIDDM. or adult-onset diabetes, results from a combination of insulin resistance and inadequate secretion of insulin w2,3x. Type 2 is the most common form, accounting for 90–95% of diabetes in developed countries. A third category, termed gestational diabetes, is the development of glucose intolerance during pregnancy w4x. Screening high-risk individuals for gestational diabetes during prenatal care has been strongly advocated for several years w4x and will not be discussed further in this review.
0009-8981r02r$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 9 - 8 9 8 1 Ž 0 1 . 0 0 7 2 2 - 7
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Screening of asymptomatic individuals for type 2 diabetes has been the subject of much controversy. The American Diabetes Association ŽADA., which previously did not support screening w5x, revised their recommendations in 1997 to favor screening w6x. What is the rationale underlying this support for screening? Because it is frequently asymptomatic, 33%–50% of those individuals with type 2 diabetes have not been diagnosed w7x. Moreover, because the onset of the disease is believed to occur 4–7 years before diagnosis, many patients with type 2 diabetes have complications of the disease by the time of clinical diagnosis w8x. The third reason is that early diagnosis and therapeutic intervention is thought to prevent or delay the onset of complications. The excellent outcomes data that clearly document the benefits of good metabolic control in individuals with the disease w9x have led to the inference that screening programs for type 2 diabetes mellitus should be instituted. This assertion, however, is not supported by any controlled study and thus a recommendation for population screening for diabetes mellitus is not an evidence-based strategy. This review will describe the significance of diabetes and examine the rationale that led to the advocation of screening for diabetes.
world is predicted to be substantially greater than the 42% rise in the developed world w12x. Therefore, by the year 2025, ) 75% of individuals with diabetes will live in developing countries. Much of this predicted gain is related to a dramatic rise in obesity. There is a large body of data linking obesity to the development of type 2 diabetes w13x. Virtually all obese individuals are insulin resistant and 60%–80% of patients with type 2 diabetes are obese. Prospective studies—such as the Nurses Cohort Study—have established that Žafter adjusting for age. body mass index ŽBMI. is the primary predictor for the development of diabetes w14x. An additional independent risk factor for diabetes is the distribution of fat. After controlling for BMI, a waist circumference ) 40 in. Ž102 cm. increases the risk of diabetes by 3.5-fold w15x. Although only 15% of obese individuals develop diabetes, the rapidly increasing prevalence of obesity in both the developed and developing world w13x makes it likely that diabetes mellitus will continue to have a major impact on world healthcare ŽFig. 1.. For example, the prevalence of obesity ŽBMI G 30 kgrm2 . in the U.S. increased from 12.0% in 1991 to 17.9% in 1998 w16x.
1.2. Epidemiology of diabetes mellitus
Individuals with diabetes are at significantly increased risk for the development of debilitating complications w17x. These are microvascular—predominantly retinopathy, nephropathy and neuropathy— and macrovascular, particularly stroke and coronary artery disease, the last resulting in acute myocardial infarction. Furthermore, acute episodes such as diabetic ketoacidosis, hyperosmolar coma, and severe hypoglycemia contribute to the morbidity and mortality of the disease. It is thus not surprising that diabetes is currently the seventh most common cause of death in the developed world w18x. This figure is likely to be an underestimate given the total number of undiagnosed cases of diabetes and the low specificity for diabetes-related causes of death, such as cerebrovascular accident and myocardial infarction. In addition to being a major cause of mortality, diabetes is the most common cause of limb amputations and end-stage renal disease w19x. After 20 years of diabetes, virtually all patients with type 1 diabetes and ) 60% of type 2 diabetes have retinopathy,
A global epidemic of diabetes is predicted for the first quarter of the 21st century. In the U.S. in 1998 approximately 6.5% of the population Žover 16 million people. were diagnosed with type 2 diabetes and a roughly equivalent number were estimated to be undiagnosed w10x. Addition of those undiagnosed yields a true prevalence in the US of ; 25 million. The prevalence is accelerating dramatically. Recent evidence reveals that the prevalence of diabetes in the US increased by 33% from 1990 to 1998 w10x, with a further 6% increase over the following year w11x. These statistics are not confined to the U.S. The worldwide prevalence of diabetes in persons G 20 years was 4.0% in 1995 and is expected to reach 5.4% Žover 300 million people. by 2025 w12x. The percentage of diabetics in 2025 in the developed world is anticipated to reach 7.6%. Although the comparable figure in the developing world is lower at 4.9%, the 170% rate of increase in the developing
1.3. Complications
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as a result of the increased prevalence of other general medical conditions seen in diabetic patients w20x. The indirect costs comprised US$17 billion for the estimated 150,000 annual deaths and US$37 billion from disability. The annual per capita health care costs for an individual with diabetes are approximately fourfold higher than those for a person who does not have diabetes w20x. Similarly, in the UK diabetes accounts for roughly 10% of the National Health Service budget Ž£49 billion.. Effective therapies to ameliorate the complications of diabetes could thus lessen the economic impact of diabetes. However, many patients have complications at the time of diagnosis of type 2 diabetes w8x. Therefore, the full impact of therapy to reduce the medical expenditure on diabetes will not be realized until the majority of patients likely to benefit from treatment are successfully identified and given appropriate medical care.
2. Tight glycemic control reduces the morbidity of diabetes
Fig. 1. Relation between BMI up to 30 and the relative risk of type 2 diabetes, hypertension, CHD and cholelithiasis. Ža. Relations for women, initially 30 to 55 years old, who were followed up to 18 years. Žb. Relations for men, initially 40–65 years old, who were followed up to 10 years w13x.
rendering diabetic retinopathy the most frequent cause of blindness in adults. Together these factors result in health care expenditures for diabetes far exceeding the prevalence of the disease in the general population. 1.4. Economic impact The costs of diabetes in the U.S. in 1992 were estimated to be US$98 billion w20x. This figure includes direct medical expenditures of US$44.1 billion and indirect costs of US$54.1 billion. The direct costs comprised US$7.7 billion for diabetes and acute glycemic care, US$11.8 billion attributed to diabetes-related complications, and US$24.6 billion
For many years it was hypothesized that the complications of diabetes were due to hyperglycemia. However, this assertion lacked convincing evidence until the last decade. Two large, randomised, well-designed multicenter trials clearly documented that improved glycemic control decreased the development of microvascular complications in individuals with type 1 w21x and type 2 diabetes w9x. These trials provide strong evidence that, regardless of the etiology, the microvascular complications of diabetes mellitus are due to hyperglycemia. The first major study to demonstrate this finding was the Diabetes Control and Complications Trial ŽDCCT., which revealed in a landmark publication in 1993 that strict glycemic control in patients with type 1 diabetes significantly diminished the incidence and progression of microvascular complications w21x. The DCCT study contained 1441 individuals who were randomly assigned to intensive glucose-lowering therapy or conventional therapy with insulin. The study period averaged 7 years. The goals of intensive therapy were evaluated by self-monitoring of blood glucose ŽSMBG. four times a day and monthly
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measurement of Hb A 1c . Median Hb A 1c concentrations were 9.1% and 7.2% for the conventional and intensive therapy groups, respectively, for a 20% overall reduction in Hb A 1c concentrations. There was a direct relationship between the Hb A 1c concentration and the prevalence of microvascular complications. Patients in the intensively treated group had a significantly lower rate of microvascular complications. Compared to the conventionally treated group, the rates of retinopathy, nephropathy and neuropathy were reduced in the intensively treated group by 76%, 39% and 60%, respectively. Although the rate of macrovascular complications was reduced slightly by intensive therapy, this decrease was not statistically significant. What about type 2 diabetes? The United Kingdom Prospective Diabetes Study ŽUKPDS. w9x was a multicenter trial to determine the impact of intensive blood glucose control in subjects with type 2 diabetes. The study enrolled 5102 patients with newly diagnosed type 2 diabetes and blood glucose concentrations were controlled with oral agents andror insulin. Although the median Hb A 1c concentration in the intensively treated group was only 13% lower than in the conventional treatment group Ž7.0% and 7.9%, respectively., the prevalence of microvascular complications was reduced by 25% w9x. Despite the demonstrated efficacy in reducing hyperglycemia, no significant decrease in macrovascular complications or diabetes-related mortality was observed in the intensively treated group in the UKPDS w9x. Addi-
tionally, intensive treatment with insulin or sulfonylureas significantly increased the number of hypoglycemic episodes. Analogous to the DCCT, the UKPDS documented the value of glycohemoglobin analysis. There was a steep increase in the risk of complications for each 1% increase in Hb A 1c concentration. Conversely, decreasing Hb A 1c by 1% reduced microvascular complications by 35% and diabetes-related mortality by 25% w9x. Together these outcomes trials clearly demonstrate the value of Hb A 1c as an integral component of the management of diabetes and its ability to predict the development of complications. Based on these studies the ADA has identified clearly defined Hb A 1c target values for glycemic control w22x. These are: normal, - 6%; treatment goal, - 7% and modify therapy if Hb A 1c ) 8%.
3. Laboratory methods for the diagnosis of diabetes mellitus The diagnosis of diabetes is established exclusively by the demonstration of increased concentrations of glucose in the blood. For many years, the oral glucose tolerance test ŽOGTT. was the sole diagnostic criterion; the cutoff was 2 SD Žstandard deviations. above the mean of the glucose concentration in healthy volunteers. In 1979 revised criteria were proposed, including fasting plasma glucose ŽFPG. G 7.8 mmolrl Ž140 mgrdl. and a 2-h post-
Table 1 Criteria for the diagnosis of diabetes mellitusa IFG
IGT
Diabetesb
(A) ADA criteria FPG G 6.1 Ž110. and - 7.0 Ž126.
2-h PG G 7.8 Ž140. and - 11.1 Ž200.
FPG G 7.0 Ž126. or 2-h PG G 11.1 Ž200. or symptoms of diabetes and casual plasma glucose concentration G 11.1 Ž200.
(B) WHO criteria FPG G 6.1 Ž110. and - 7.0 Ž126. and 2-h PG - 7.8 Ž- 140. Žif measured.
FPG - 7.0 Ž126. Žif measured. and 2-h PG G 7.8 Ž140. and - 11.1 Ž200.
FPG G 7.0 Ž126. or 2-h PG G 11.1 Ž200. or both
See text for explanation. FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; 2-h PG, 2-h postload glucose. Adapted from Refs. w6,23x. a Glucose concentrations are in mmolrl Žmgrdl.. b If one of these criteria is met, diagnosis of diabetes must be confirmed by repeat testing on a subsequent day. The FPG test is preferred due to ease of administration.
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load glucose value G 11.1 mmolrl Ž200 mgrdl. w5x. Because the fasting and 2-h values were not equivalent, the criteria were modified in 1997 w6x. Based on a correlation between blood glucose concentrations and the risk of subsequent complications, the cutoff was lowered to FPG G 7.0 mmolrl Ž126 mgrdl. ŽTable 1.. Although the OGTT remained a diagnostic criterion, its use was discouraged w6x. Similarly, the World Health Organization ŽWHO. revised their diagnostic criteria ŽTable 1. w23x. Although some similarities to the ADA criteria are observed, the WHO continue to recommend the OGTT, albeit in an abbreviated form Žglucose need be measured only in a fasting sample and 2 h after a 75-g oral glucose load Žsee Ref. w23x for details..
4. Screening The ADA recommends screening for diabetes in all asymptomatic individuals over the age of 45 years by measurement of FPG w24x. If FPG is below 6.1 mmolrl Ž110 mgrdl., repeat testing is recommended at 3-year intervals. For individuals with defined risk factors for diabetes, including family history or obesity Žsee Table 2 for complete list., screening prior to the age of 45 years is recommended. Table 2 Criteria for testing for diabetes in asymptomatic, undiagnosed individuals Ž1. Testing for diabetes should be considered in all individuals at age 45 years and above and, if normal, it should be repeated at 3-year intervals. Ž2. Testing should be considered at a younger age or be carried out more frequently in individuals who: Ža. are obese Ž G120% desirable body weight or a BMIG127 kgrm2 . Žb. have a first-degree relative with diabetes Žc. are members of a high-risk ethnic population Že.g., African American, Hispanic American, Native American, Asian American, Pacific Islander. Žd. have delivered a baby weighing G9 lb. or have been diagnosed with GDM Že. are hypertensive ŽBPG140r90 mm Hg. Žf. have HDL cholesterol G 35 mgrdl Ž0.90 mmolrl. andror a triglyceride G 250 mgrdl Ž2.82 mmolrl. Žg. on previous testing, had IGT or IFG Adapted from Ref. w24x.
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4.1. Screening for type 2 diabetes 4.1.1. Fasting plasma glucose Measurement of FPG requires an overnight fast of G 8 h, during which time water, but not food, may be consumed. Glucose concentrations decrease ex vivo by approximately 5–7%rh due to glycolysis w25x. Unless the venous blood is subjected to centrifugation within 60 min to remove the cells, additives such as sodium fluoride or lithium iodoacetate should be included in blood collection tubes to inhibit glycolysis w25x. Plasma glucose is accurately measured by enzymatic assays. The vast majority of analyses in the U.S. use methods employing hexokinase or glucose oxidase w26x. Both methods have low imprecision, with intra-assay CVs Žcoefficients of variability. of - 4% at a plasma glucose concentration of ; 8.2 mmolrl Ž147 mgrdl.. Comparison of the two assays in 240 subjects yielded mean glucose concentrations of 101.6 " 4 and 96.7 q " 3.9 mgrdl for hexokinase and glucokinase, respectively, with an inter-assay difference of approximately 5% w27x. Glucose concentrations in whole blood can be rapidly measured with meters that are used by patients for self-monitoring, in hospitals at the patient’s bedside or in clinics and physician’s offices w26x. However, due to their large imprecision, these meters should not be used for screening or diagnosis. Although plasma glucose assays in the central laboratory have low imprecision, the biological variability for glucose is large. For example, consecutive determinations of FPG revealed an intra-individual CV of 7% in 246 non-diabetic patients w28x. Applying this biologic variability to a true glucose value of 7.0 mmolrl Ž126 mgrdl. would produce 95% CI Žconfidence intervals. of 6.0–8.0 mmolrl Ž108–144 mgrdl.. An additional factor that makes a significant contribution to variability is the diurnal fluctuation in FPG concentrations. This was demonstrated by evaluating 12,882 participants in the Third National Health and Nutrition Examination Survey ŽNHANES III. aged 20 years or older who had no previously diagnosed diabetes w29x. Subjects were randomly assigned to morning or afternoon FPG determinations. Mean FPG concentrations were significantly higher in the morning group w5.41 mmolrl Ž97.4 mgrdl.x
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than in the afternoon group w5.12 mmolrl Ž92.4 mgrdl.x. These differences resulted in a prevalence of diabetes wFPG G 7.0 mmolrl Ž126 mgrdlx in the afternoon group half of that for the morning group w29x. To obtain the same prevalence of diabetes as the morning-examined participants, a cutoff for FPG of 6.3 mmolrl Ž114 mgrdl. was required for the afternoon group. These results have major implications for diabetes screening, as many patients are seen by their physicians in the afternoon and approximately half of all cases of undiagnosed diabetes in these patients will be missed. Therefore, we recommend that screening for type 2 diabetes be performed in the morning whenever feasible.
4.1.2. The oral glucose tolerance test Previously the OGTT was the primary means of diagnosing diabetes. The ADA no longer recommends its use in non-pregnant individuals, but an abbreviated version forms an important component of WHO recommendations w23x. The protocol for performing an OGTT requires an overnight fast of 8–14 h. After obtaining a fasting blood sample, the patient receives 75 g of glucose orally and blood is sampled 2 h later. Plasma glucose concentrations G 11.1 mmolrl Ž200 mgrdl. in the 2-h sample are diagnostic of diabetes. The WHO recommends that the OGTT be used when FPG is in the impaired fasting glucose ŽIFG. range of 6.1–6.9 mmolrl Ž110–125 mgrdl.. The ADA advocates elimination of the OGTT because it has poor reproducibility, is time-consuming and expensive, requires extensive patient preparation, lacks standardization of the glucose load and requires multiple venipuncture w30x. The poor reproducibility is exemplified by a study of 524 subjects without a history of diabetes who were evaluated with two OGTTs performed 2 to 6 weeks apart w31x. Of the 198 patients classified with impaired glucose tolerance ŽIGT. by the first OGTT, 78 Ž39%. and 25 Ž13%. were classified with normal glucose tolerance and diabetes, respectively, by the second OGTT. If the initial OGTT is used as the gold standard, repetition of the OGTT will misclassify half of the subjects close to the cutoff. However, the OGTT is more sensitive than FPG because impaired release of insulin in response to glucose develops earlier in the
course of type 2 diabetes than increased fasting glucose. Therefore, screening for diabetes by the OGTT yields a prevalence of diabetes higher than that obtained by FPG. For example, Harris et al. w32x detected a prevalence of undiagnosed diabetes in NHANES III of 6.4% and 4.4% by WHO and ADA criteria, respectively. However, individuals classified by ADA criteria were observed to be more hyperglycemic and had higher Hb A 1c concentrations w32x. Therefore, use of the OGTT remains contentious. 4.1.3. Hb A 1c All proteins undergo non-enzymatic glycation. Addition of glucose to hemoglobin results in the formation of glycohemoglobin. A component of glycohemoglobin, Hb A 1c , is formed by the addition of glucose to the N-terminal valine residue of the bchain of hemoglobin A ŽHbA.. Because the average lifespan of an erythrocyte is 120 days, the Hb A 1c concentration—expressed as the percentage of total hemoglobin—reflects the mean glucose concentration over the preceding 6 to 8 weeks w26x. What is the rationale for screening for diabetes with Hb A 1c? Because it reflects the integrated glucose concentration over time, Hb A 1c is not subject to the wide diurnal fluctuations seen with blood glucose concentrations. Patients do not need to be fasting at the time of blood sampling and the intraindividual variability is low. Perhaps most importantly, the Hb A 1c value correlates directly with microvascular complications and predicts their development. Together these factors mitigate for the use of Hb A 1c for screening of asymptomatic individuals for diabetes. It has been argued that the large imprecision and lack of standardization of Hb A 1c assays precludes its use as a screening modality. The significant role of Hb A 1c in the DCCT led to the establishment of the National Glycohemoglobin Standardization Program ŽNGSP. in 1996. The goal of the NGSP is to standardize Hb A 1c assays to DCCT-equivalent values. Working closely with manufacturers of instruments for Hb A 1c analysis and monitoring progress with proficiency material from the College of American Pathologists ŽCAP., the NGSP has made substantial progress towards attaining this goal Ždetailed information is available at the NGSP website: http:rrwww.missouri.edur; diabetesrngsp.html...
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This progress suggests that Hb A 1c may be useful for screening and this thesis is supported by preliminary studies. For example, David Goldstein’s group screened 6559 participants in NHANES III by FPG and Hb A 1c . Diabetes was diagnosed if FPG G 7.0 mmolrl. Selecting a cutoff for Hb A 1c of 5.6% Ž1 SD above the normal mean. yielded a sensitivity of 83.4% and specificity of 84.4% for the diagnosis of diabetes w33x. If a cutoff of 6.1% Ž2 SD above the normal mean. was used, sensitivity and specificity were 63.2% and 97.4%, respectively. An alternative strategy using a two-step procedure for screening has been proposed by Davidson et al. w34x: individuals with FPG of 6.1–7.7 mmolrl Ž110– 139 mgrdl. should be followed with analysis of Hb A 1c . Diabetes would be diagnosed only if the Hb A 1c value on two separate occasions was 1% above the upper limit of the reference interval for the assay used. The rationale underlying this proposal is that a large percentage of individuals with FPG values ) 7.0 mmolrl Ž126 mgrdl. do not have evidence of long-term hyperglycemia by Hb A 1c analysis w34x. A limitation of Hb A 1c analysis is possible interference in the assay. Hemoglobin variants—such as HbS, HbC and HbE—and chemically modified derivatives, such as carbamyl-hemoglobin, may yield spurious results when Hb A 1c is measured w35x. Moreover, any condition that alters erythrocyte halflife, including hemolysis, hemorrhage or transfusion, result in Hb A 1c values that do not reflect long-term glycemia w35x. It would not be possible to use Hb A 1c for screening or diagnosis in patients with these conditions.
4.4. Screening for type 1 diabetes Is there a role for screening for type 1 diabetes? Although the prevalence is much lower than that of type 2 diabetes, the type 1 form of the disease is also becoming more common. The global incidence of type 1 diabetes is increasing by approximately 3% per year w36x. Moreover, ; 10% of individuals classified with type 2 diabetes have islet autoantibody markers of type 1 diabetes w37,38x. These patients with possible slow-onset type 1 diabetes are usually
67
not adequately controlled with oral hypoglycemic agents and require insulin therapy for good metabolic control. Type 1 diabetes is an autoimmune disease. Autoantibodies are produced to several islet autoantigens, including insulin, the 65-kDa glutamic acid decarboxylase isoform ŽGAD65. and the protein tyrosine phosphatase IA-2 w39x. The simultaneous detection in the blood of all three autoantibodies in first-degree relatives of individuals with type 1 diabetes is highly predictive of the development of the disease w40,41x. However, no therapeutic intervention has been identified that will prevent or significantly delay the onset of the disease. Moreover, unlike type 2 diabetes which is frequently clinically silent, type 1 diabetes usually exhibits a dramatic clinical onset. Therefore, there is no current role for general population screening for type 1 diabetes by autoantibody testing. Moreover, the ADA does not recommend screening for unaffected first-degree relatives of individuals with type 1 diabetes because of the lack of evidence as to how to proceed after a positive test w24x. Islet autoantibody screening of first-degree relatives is currently used in clinical trials, several of which are underway. Large studies of diabetes prevention, such as the Diabetes Prevention Trial Type-1 ŽDPT-1. w42x, are likely to reveal whether the onset of type 1 diabetes can be delayed by the institution of therapy prior to the onset of clinical symptoms.
5. Conclusions Screening for diabetes is a highly contentious topic. In the absence of data to support widespread population screening, a somewhat intuitive approach has been taken by the ADA in its recommendations w24x. Laboratory medicine has made an essential contribution to the success of diabetes screening. Clinical laboratories have facilitated marked improvements in glucose assays, substantially reducing the imprecision. Currently, considerable effort is directed towards Hb A 1c standardization. In addition to the NGSP, the International Federation for Clinical Chemistry ŽIFCC. has joined the standardization effort and two candidate reference methods for Hb A 1c have been developed w43x. Initial comparisons appear
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to indicate a linear relationship between the IFCC and NGSP Laboratory Networks. These advances augur well. We eagerly await long-term outcomes studies to provide an evidence-based approach to finally resolve the question of whether to institute widespread population screening for diabetes.
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w34x
w35x
w36x
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