Tests of Glycemia in Diabetes

POSITION STATEMENT

AMERICAN DIABETES ASSOCIATION

onitoring of glycemic status, as which provide a comprehensive review of to increasing use of SMBG include cost performed by patients and health the subject (3,4). of testing, inadequate understanding by M care providers, is considered a both health care providers and patients cornerstone of diabetes care. Results of Recommendations about the health benefits and proper use monitoring are used to assess the efficacy 1. Based principally on the DCCT results, it of SMBG results, patient psychological of therapy and to guide adjustments in is recommended that most individuals and physical discomfort associated with medical nutrition therapy (MNT), exer- with diabetes should attempt to achieve finger-prick blood sampling, and incon- cise, and medications to achieve the best and maintain blood glucose levels as venience of testing in terms of time possible blood glucose control. close to normal as is safely possible. Be- requirements, physical setting, and This position statement presents the cause most patients with type 1 diabetes complexity of the technique. recommendations of the American Diabe- can achieve this goal only by using Given the importance of SMBG to di- tes Association on the tests used most SMBG, all treatment programs should abetes care, government, third-party widely in monitoring the glycemic status encourage SMBG for routine daily mon- payers, and others should strive to make of people with diabetes and addresses itoring. Daily SMBG is especially impor- the procedure readily accessible and af- both patient and physician/laboratory- tant for patients treated with insulin or fordable for all patients who require it. based testing. It does not address tests for sulfonylureas to monitor for and prevent Thus, SMBG should be an important diabetes screening and diagnosis. The asymptomatic hypoglycemia. Fre- component of any health care benefits recommendations are based on both the quency and timing of glucose monitor- package. American Diabetes Association’s techni- ing should be dictated by the needs and cal review, “Tests of Glycemia in Diabe- goals of the individual patient, but for 3. Because the accuracy of SMBG is in- tes” (1), and the National Academy of most patients with type 1 diabetes, strument and user dependent, it is im- Clinical Biochemistry’s laboratory medi- SMBG is recommended three or more portant for health care providers to cine practice guideline on the subject (2). times daily. The optimal frequency of evaluate each patient’s monitoring SMBG for patients with type 2 diabetes technique, both initially and at regular is not known, but should be sufficient to intervals thereafter. Use of calibration BLOOD GLUCOSE TESTING facilitate reaching glucose goals. Thus, and control solutions on a regular ba- BY PATIENTS — Within only a few the frequency of surveillance should be sis by patients helps ensure accuracy years, self-monitoring of blood glucose such that risks for both hyper- and hy- of results. In addition, because labora- (SMBG) by patients has revolutionized poglycemic episodes are minimized. tory methods measure plasma glucose, management of diabetes. Using SMBG, When adding to or modifying therapy, most blood glucose monitors ap- patients with diabetes can work to achieve type 1 and type 2 diabetic patients proved for home use and some test and maintain specific glycemic goals. should test more often than usual. The strips now calibrate blood glucose Given the results of the Diabetes Control role of SMBG in stable diet-treated pa- readings to plasma values. Plasma glu- and Complications Trial (DCCT) and tients with type 2 diabetes is not known. cose values are 10–15% higher than other studies, there is broad consensus on 2. SMBG is recommended for all insulin- whole blood glucose values, and it is the health benefits of normal or near- treated patients with diabetes. SMBG crucial that people with diabetes know normal blood glucose levels and on the may be desirable in patients treated with whether their monitor and strips pro- importance, especially in insulin-treated sulfonylureas or other insulin secreta- vide whole blood or plasma results. patients, of SMBG in treatment efforts de- gogues and in all patients not achieving 4. Optimal use of SMBG requires proper signed to achieve such glycemic goals. glycemic goals. Data indicate that only a interpretation of the data. Patients The subject of SMBG has been ad- minority of patients perform SMBG. Ef- should be taught how to use the data to dressed extensively by two American Di- forts should be made to substantially in- adjust MNT, exercise, or pharmacologi- abetes Association Consensus Conferences, crease appropriate use of SMBG. Barriers cal therapy to achieve specific glycemic ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● goals. Health professionals should evaluate at regular intervals the patient’s The recommendations in this paper are based on the evidence reviewed in the following publication: Tests of glycemia in diabetes (Technical Review). Diabetes Care 18:896–909, 1995. ability to use SMBG data to guide treat- The initial draft of this paper was prepared by David E. Goldstein, MD, Chair; Randie R. Little, PhD; ment. Although a number of SMBG Rodney A. Lorenz, MD; John I. Malone, MD; David M. Nathan, MD; and Charles M. Peterson, MD. The paper methods store test results and with a was peer-reviewed, modified, and approved by the Professional Practice Committee and the Executive computer interface can provide sophis- Committee, November 1996. Most recent review/revision, 2003. Abbreviations: DCCT, Diabetes Control and Complications Trial; GSA, glycated serum albumin; GSP, ticated analyses of blood glucose data, it glycated serum protein; MNT, medical nutrition therapy; SMBG, self-monitoring of blood glucose. is not known whether use of these data © 2004 by the American Diabetes Association. management systems yields better glu-

DIABETES CARE, VOLUME 27, SUPPLEMENT 1, JANUARY 2004 S91 Position Statement

cose control than patient review of referred method of monitoring glycemic sion to assessment of glycemia. With a sults recorded in a logbook. status day-to-day. single measurement, each of these tests can quantify average glycemia over weeks BLOOD GLUCOSE TESTING BY Urine/blood ketone testing and months, thereby complementing HEALTH CARE PROVIDERS Ketone testing is an important part of mon- day-to-day testing. FOR ROUTINE OUTPATIENT itoring in type 1 diabetic patients, in preg- MANAGEMENT OF DIABETES nancy with pre-existing diabetes, and in Glycated hemoglobin (GHb) testing gestational diabetes. The presence of ke- GHb, also referred to as glycohemoglobin, Recommendations tones may indicate impending or even es- glycosylated hemoglobin, HbA1c, A1C, or tablished ketoacidosis, a condition that HbA1, is a term used to describe a series of requires immediate medical attention. stable minor hemoglobin components 1. Blood glucose testing (e.g., laboratory Patients with type 1 diabetes should test for formed slowly and nonenzymatically from glucose or finger-stick glucose) should ketones during acute illness or stress or hemoglobin and glucose. The rate of forma- be available to providers for use as when blood glucose levels are consistently tion of GHb is directly proportional to the needed. With the availability of SMBG elevated (e.g., Ͼ300 mg/dl [Ͼ16.7 mmol/ ambient glucose concentration. Since and glycated protein testing, routine lab- l]), during pregnancy, or when any symp- erythrocytes are freely permeable to glu- oratory blood glucose testing by health toms of ketoacidosis, such as nausea, cose, the level of GHb in a blood sample care providers should no longer be used vomiting, or abdominal pain, are present. provides a glycemic history of the previous to assess glycemic control except to sup- Ketones are normally present in 120 days, the average erythrocyte life span. plement information obtained from urine, but concentrations are usually be- GHb most accurately reflects the previous other testing methods and to test the ac- low the limit of detectability with routine 2-3 months of glycemic control. curacy of SMBG. When adjusting oral testing methods. However, positive ke- Many different types of GHb assay glucose-lowering medication(s) in a pa- tone readings are found in normal indi- methods are available to the routine clini- tient not taking insulin, laboratory test- viduals during fasting and in up to 30% of cal laboratory. Methods differ considerably ing also may be appropriate. first morning urine specimens from preg- with respect to the glycated components 2. Comparisons between results from nant women. Urine ketone tests using ni- measured, interferences, and nondiabetic patient self-testing of blood glucose in troprusside-containing reagents can give range. Glycated hemoglobin is often re- the clinic and simultaneous laboratory false-positive results in the presence of ported as hemoglobin A1c. HbA1c has be- testing are useful to assess the accuracy several sulfhydryl drugs, including the come the preferred standard for assessing of patient results. If such testing is per- antihypertensive drug captopril. False- glycemic control. In referring to this test, formed by health care providers using negative readings have been reported the term “A1C test” will be used. portable capillary blood testing de- when test strips have been exposed to air The A1C test has been shown to predict vices rather than standard hospital or for an extended period of time or when the risk for the development of many of the clinic laboratory methods, rigorous urine specimens have been highly acidic, chronic complications in diabetes, analo- quality control procedures should be such as after large intakes of ascorbic acid. gous to using cholesterol determinations to used. Participation in the College of Ketone testing materials should be predict the risk for development of car- American Pathologists voluntary pro- available in the office/clinic setting. Health diovascular disease. However, optimal ficiency testing program for home-use care professionals should be aware, how- use of the A1C test for this purpose re- testing devices is recommended. ever, that currently available urine ketone quires the standardization of A1C test as- 3. Continuous ambulatory blood glucose tests are not reliable for diagnosing or says. Without standardization, reported monitoring may be used to determine monitoring treatment of ketoacidosis. results between laboratories may not be 24-h blood glucose patterns and to de- Blood ketone testing methods that quan- comparable, even if both laboratories use tect unrecognized hypoglycemia; how- tify ␤-hydroxybutyric acid, the predomi- the same assay method. The National Gly- ever, its role in improving diabetes nant ketone body, are available and are cohemoglobin Standardization Program outcomes remains to be established. preferred over urine ketone testing for di- (http://www.ngsp.org), sponsored in part agnosing and monitoring ketoacidosis. by the American Diabetes Association to URINE GLUCOSE Home tests for ␤-hydroxybutyric acid are standardize A1C test determinations to TESTING — SMBG has supplanted available. DCCT values, began in mid-1996. On an urine glucose testing for most patients. annual basis, manufacturers of A1C test Urine glucose testing by patients in the GLYCATED PROTEIN assay methods are awarded a “certificate of home setting consists of semiquantitative TESTING — Blood and urine glucose traceability to the DCCT reference measurements based on single voidings testing and urine ketone testing provide method” if their assay method passes rig- or, less often, by more quantitative useful information for day-to-day man- orous testing criteria for precision and ac- “blocks” collected over 4–24 h. The ratio- agement of diabetes. However, these tests curacy. It is desirable that laboratories use nale is that urinary glucose values reflect cannot provide the patient and health only A1C test assay methods that have mean blood glucose during the period of care team with a quantitative and reliable passed certification testing. It is also de- urine collection. However, despite the rel- measure of glycemia over an extended pe- sirable that all laboratories performing atively low cost and ease of specimen col- riod of time. Measurements of glycated A1C testing participate in the College of lection, the well-described limitations of proteins, primarily hemoglobin and se- American Pathologists proficiency testing urine glucose testing make SMBG the pre- rum proteins, have added a new dimen- survey for A1C testing started in mid-

S92 DIABETES CARE, VOLUME 27, SUPPLEMENT 1, JANUARY 2004 Tests of Glycemia

1996 (5), which uses whole-blood speci- Table 1—Correlation between A1C level and preceding 1-2 weeks, while a single A1C mens. Regardless of the assay method mean plasma glucose levels (4) test provides an index of glycemic status type and specific analyte qualified, all re- over a considerably longer period of time, sults should be reported as “% HbA1c” or Mean plasma glucose 2-3 months. “% HbA1c equivalents.” Measurement of GSP (including fruc- A1C testing should be performed rou- A1C (%) mg/dl mmol/l tosamine) has been used to document rel- tinely in all patients with diabetes, first to 6 135 7.5 atively short-term changes (e.g., 1–2 document the degree of glycemic control at 7 170 9.5 weeks) in glycemic status, such as in dia- initial assessment, then as part of continu- 8 205 11.5 betic pregnancy or after major changes in ing care. Since the A1C test reflects a mean 9 240 13.5 therapy. However, further studies are glycemia over the preceding 2–3 months, 10 275 15.5 needed to determine if the test provides measurement approximately every 3 11 310 17.5 useful clinical information in these months is required to determine whether a 12 345 19.5 situations. patient’s metabolic control has reached and Measurement of GSP, regardless of been maintained within the target range. the specific assay method, should not be Thus, regular A1C testing permits detection ciation recommends that the goal of ther- considered equivalent to the A1C test, of departures from the target range in a apy should be an A1C result of Ͻ7% and since it only indicates glycemic control timely fashion. For any individual patient, that physicians should reevaluate and, in over a short period of time. Therefore, the frequency of A1C testing should be de- most cases, significantly change the treat- GSP assays would have to be performed pendent on the treatment regimen used and ment regimen in patients with A1C test on a monthly basis to gather the same in- on the judgment of the clinician. In the ab- results consistently above goals. Again, formation as measured by the A1C test sence of well-controlled studies that suggest these specific A1C values apply only to three to four times a year. Unlike the A1C adefinite testing protocol, expert opinion assay methods that are certified as trace- test, GSP has not yet been shown to be recommends A1C testing at least two times able to the DCCT reference method. related to the risk of the development or a year in patients who are meeting treatment progression of chronic complications of goals (and who have stable glycemic con- Glycated serum protein (GSP) diabetes. trol) and more frequently (quarterly assess- Because the turnover of human serum al- ment) in patients whose therapy has bumin is much shorter (half-life of 14–20 changed or who are not meeting glycemic days) than that of hemoglobin (erythro- goals. cyte life span of 120 days), the degree of References 1. Goldstein DE, Little RR, Lorenz RA, Ma- Proper interpretation of A1C test re- glycation of serum proteins (mostly albu- lone JI, Nathan D, Peterson CM: Tests of sults requires that health care providers min) provides an index of glycemia over a glycemia in diabetes (Technical Review). understand the relationship between test shorter period of time than does glycation Diabetes Care 18:896–909, 1995 results and average blood glucose, kinet- of hemoglobin. Measurements of total 2. Sacks DS, Bruns DE, Goldstein DE, Ma- ics of the A1C test, and specific assay lim- GSP and glycated serum albumin (GSA) claren NK, McDonald JM, Parrott M: itations. Data from the DCCT relating correlate well with one another and with Guidelines and recommentations for labo- A1C test results to mean plasma glucose measurements of glycated hemoglobin ratory analyses in the diagnosis and man- levels appear in Table 1 (6), but these data (A1C test). In situations where the A1C agement of diabetes mellitus. Diabetes Care should be used with caution if the A1C test cannot be measured or may not be 25:750–786, 2002 test assay method is not certified as trace- useful (e.g., hemolytic anemias), the GSP 3. American Diabetes Association: Self-monitoring of blood glucose (Consensus State- able to the DCCT reference method. assay may be of value in the assessment of ment). Diabetes Care 17:81–86, 1994 A1C test values in patients with dia- the treatment regimen. Several methods 4. American Diabetes Association: Self-moni- betes are a continuum; they range from have been described that quantify either toring of blood glucose (Consensus State- normal in a small percentage of patients total GSP or total GSA. One of the most ment). Diabetes Care 10:93–99, 1987 whose average blood glucose levels are in widely used is called the fructosamine as- 5. Little RR, Rohlfing CL, Wiedmeyer H-M, or close to the normal range to markedly say. Values for GSP vary with changes in Myers GL, Sacks DB, Goldstein DE: The elevated values, e.g., Ͼ9.5%, in some pa- the synthesis or clearance of serum pro- National Glycohemoglobin Standardiza- tients, reflecting an extreme degree of hy- teins that can occur with acute systemic tion Program (NGSP): a five-year progress perglycemia. Specific treatment goals illness or with liver disease. In addition, report. Clin Chem 47:1985–1992, 2001 should be individualized, but one must there is continuing debate as to whether 6. Rohlfing CL, Wiedmeyer HM, Little RR, England JD, Tennill A, Goldstein DE: De- take into account the results of studies, fructosamine assays should be corrected fining the relationship between plasma glu- such as the DCCT, showing a direct rela- for serum protein or serum albumin con- cose and HbA : analysis of glucose profiles tionship between A1C test values and the centrations. 1c and HbA1c in the Diabetes Control and risk of many of the chronic complications A single measurement of GSP pro- Complications Trial. Diabetes Care 25:275– of diabetes. The American Diabetes Asso- vides an index of glycemic status over the 278, 2002

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