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      Hemoglobin A1c May Be an Inadequate Diagnostic Tool for Diabetes Mellitus in Anemic Subjects

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          Recently, a hemoglobin A1c (HbA1c) level of 6.5% has been determined to be a criterion for diabetes mellitus (DM), and it is a widely used marker for the diagnosis of DM. However, HbA1c may be influenced by a number of factors. Anemia is one of the most prevalent diseases with an influence on HbA1c; however, its effect on HbA1c varies based on the variable pathophysiology of anemia. The aim of this study was to determine the effect of anemia on HbA1c levels.


          Anemic subjects ( n=112) and age- and sex-matched controls ( n=217) who were drug naive and suspected of having DM were enrolled. The subjects underwent an oral glucose tolerance test and HbA1c simultaneously. We compared mean HbA1c and its sensitivity and specificity for diagnosing DM between each subgroup.


          Clinical characteristics were found to be similar between each subgroup. Also, when glucose levels were within the normal range, the difference in mean HbA1c was not significant ( P=0.580). However, when plasma glucose levels were above the diagnostic cutoff for prediabetes and DM, the mean HbA1c of the anemic subgroup was modestly higher than in the nonanemic group. The specificity of HbA1c for diagnosis of DM was significantly lower in the anemic subgroup ( P<0.05).


          These results suggest that the diagnostic significance of HbA1c might be limited in anemic patients.

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          Disparities in HbA1c levels between African-American and non-Hispanic white adults with diabetes: a meta-analysis.

          Among individuals with diabetes, a comparison of HbA(1c) (A1C) levels between African Americans and non-Hispanic whites was evaluated. Data sources included PubMed, Web of Science, the Cumulative Index to Nursing and Allied Health, the Cochrane Library, the Combined Health Information Database, and the Education Resources Information Center. We executed a search for articles published between 1993 and 2005. Data on sample size, age, sex, A1C, geographical location, and study design were extracted. Cross-sectional data and baseline data from clinical trials and cohort studies for African Americans and non-Hispanic whites with diabetes were included. Diabetic subjects aged <18 years and those with pre-diabetes or gestational diabetes were excluded. We conducted a meta-analysis to estimate the difference in the mean values of A1C for African Americans and non-Hispanic whites. A total of 391 studies were reviewed, of which 78 contained A1C data. Eleven had data on A1C for African Americans and non-Hispanic whites and met selection criteria. A meta-analysis revealed the standard effect to be 0.31 (95% CI 0.39-0.25). This standard effect correlates to an A1C difference between groups of approximately 0.65%, indicating a higher A1C across studies for African Americans. Grouping studies by study type (cross-sectional or cohort), method of data collection for A1C (chart review or blood draw), and insurance status (managed care or nonmanaged care) showed similar results. The higher A1C observed in this meta-analysis among African Americans compared with non-Hispanic whites may contribute to disparity in diabetes morbidity and mortality in this population.
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            Effect of iron deficiency anemia on the levels of hemoglobin A1c in nondiabetic patients.

            The major form of glycohemoglobin is hemoglobin A1c (HbA1c). The HbA1c fraction is abnormally elevated in chronic hyperglycemic diabetic patients and correlates positively with glycemic control. Previous studies suggest that iron deficiency anemia (IDA) affects the levels of HbA1c. The aim of this study was to determine the effect of IDA on HbA1c levels in nondiabetic patients. The population studied consisted of 50 patients (30 women, 20 men, mean age 35.7 +/- 11.9 years) with IDA and 50 healthy subjects that were matched for age and sex. Patients who had glucose tolerance abnormalities (impaired glucose tolerance or diabetes mellitus), hemoglobinopathies, hemolytic anemia, chronic alcohol ingestion and chronic renal failure were excluded from the study. Hematologic investigations, fasting and postprandial glucose and HbA1c levels were measured in all subjects before iron therapy. All patients with IDA were treated with iron 100 mg/day for 3 months. We repeated the laboratory investigation after iron therapy. Before iron treatment, the mean HbA1c (7.4 +/- 0.8%) level in patients with IDA was higher than in a healthy group (5.9% +/- 0.5) (p < 0.001). In patients with IDA, HbA1c decreased significantly after iron treatment from a mean of 7.4% +/- 0.8 to 6.2% +/- 0.6 (p < 0.001). Iron deficiency must be corrected before any diagnostic or therapeutic decision is made based on HbA1c.
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              Executive Summary: Standards of Medical Care in Diabetes—2011

              Current criteria for the diagnosis of diabetes A1C ≥6.5%. The test should be performed in a laboratory using a method that is National Glycohemoglobin Standardization Program (NGSP)-certified and standardized to the Diabetes Control and Complications Trial (DCCT) assay fasting plasma glucose (FPG) ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h, or 2-h plasma glucose ≥200 mg/dl (11.1 mmol/l) during an oral glucose tolerance test (OGTT). The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dl (11.1 mmol/l) in the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing. Testing for diabetes in asymptomatic patients Testing to detect type 2 diabetes and assess risk for future diabetes in asymptomatic people should be considered in adults of any age who are overweight or obese (BMI ≥25 kg/m2) and who have one or more additional risk factors for diabetes (see Table 4 of the “Standards of Medical Care in Diabetes—2011”). In those without these risk factors, testing should begin at age 45 years. (B) If tests are normal, repeat testing carried out at least at 3-year intervals is reasonable. (E) To test for diabetes or to assess risk of future diabetes, A1C, FPG, or 2-h 75-g OGTT are appropriate. (B) In those identified with increased risk for future diabetes, identify and, if appropriate, treat other cardiovascular disease (CVD) risk factors. (B) Detection and diagnosis of gestational diabetes mellitus (GDM) Screen for undiagnosed type 2 diabetes at the first prenatal visit in those with risk factors, using standard diagnostic criteria. (B) In pregnant women not known to have diabetes, screen for GDM at 24–28 weeks of gestation, using a 75-g 2-h OGTT and the diagnostic cut points in Table 6 of the “Standards of Medical Care in Diabetes—2011”. (B) Screen women with GDM for persistent diabetes 6–12 weeks postpartum. (E) Women with a history of GDM should have lifelong screening for the development of diabetes or prediabetes at least every 3 years. (E) Prevention/delay of type 2 diabetes Patients with impaired glucose tolerance (IGT) (A), impaired fasting glucose (IFG) (E), or an A1C of 5.7–6.4% (E) should be referred to an effective ongoing support program targeting weight loss of 7% of body weight and increasing physical activity to at least 150 min/week of moderate activity such as walking. Follow-up counseling appears to be important for success. (B) Based on potential cost-savings of diabetes prevention, such programs should be covered by third-party payors. (E) Metformin therapy for prevention of type 2 diabetes may be considered in those at highest risk for developing diabetes, such as those with multiple risk factors, especially if they demonstrate progression of hyperglycemia (e.g. A1C ≥6%) despite lifestyle interventions. (B) Monitoring for the development of diabetes in those with prediabetes should be performed every year. (E) Glucose monitoring Self-monitoring of blood glucose (SMBG) should be carried out three or more times daily for patients using multiple insulin injections or insulin pump therapy. (A) For patients using less-frequent insulin injections, non-insulin therapies, or medical nutrition therapy (MNT) alone, SMBG may be useful as a guide to the success of therapy. (E) To achieve postprandial glucose targets, postprandial SMBG may be appropriate. (E) When prescribing SMBG, ensure that patients receive initial instruction in, and routine follow-up evaluation of, SMBG technique and their ability to use data to adjust therapy. (E) Continuous glucose monitoring (CGM) in conjunction with intensive insulin regimens can be a useful tool to lower A1C in selected adults (age ≥25 years) with type 1 diabetes. (A) Although the evidence for A1C-lowering is less strong in children, teens, and younger adults, CGM may be helpful in these groups. Success correlates with adherence to ongoing use of the device. (C) CGM may be a supplemental tool to SMBG in those with hypoglycemia unawareness and/or frequent hypoglycemic episodes. (E) A1C Perform the A1C test at least two times a year in patients who are meeting treatment goals (and who have stable glycemic control). (E) Perform the A1C test quarterly in patients whose therapy has changed or who are not meeting glycemic goals. (E) Use of point-of-care testing for A1C allows for timely decisions on therapy changes, when needed. (E) Glycemic goals in adults Lowering A1C to below or around 7% has been shown to reduce microvascular and neuropathic complications of diabetes and, if implemented soon after the diagnosis of diabetes, is associated with long-term reduction in macrovascular disease. Therefore, a reasonable A1C goal for many nonpregnant adults is 35 kg/m2 and type 2 diabetes, especially if the diabetes or associated comorbidities are difficult to control with lifestyle and pharmacologic therapy. (B) Patients with type 2 diabetes who have undergone bariatric surgery need life-long lifestyle support and medical monitoring. (E) Although small trials have shown glycemic benefit of bariatric surgery in patients with type 2 diabetes and BMI of 30–35 kg/m2, there is currently insufficient evidence to generally recommend surgery in patients with BMI 64 years of age previously immunized when they were 5 years ago. Other indications for repeat vaccination include nephrotic syndrome, chronic renal disease, and other immunocompromised states, such as after transplantation. (C) Hypertension/blood pressure control Screening and diagnosis Blood pressure should be measured at every routine diabetes visit. Patients found to have systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg should have blood pressure confirmed on a separate day. Repeat systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg confirms a diagnosis of hypertension. (C) Goals A goal systolic blood pressure 50 mg/dl, and triglycerides 100 mg/dl or in those with multiple CVD risk factors. (E) In individuals without overt CVD, the primary goal is an LDL cholesterol 40 mg/dl (1.0 mmol/l) in men and >50 mg/dl (1.3 mmol/l) in women are desirable. However, LDL cholesterol–targeted statin therapy remains the preferred strategy. (C) If targets are not reached on maximally tolerated doses of statins, combination therapy using statins and other lipid-lowering agents may be considered to achieve lipid targets but has not been evaluated in outcome studies for either CVD outcomes or safety. (E) Statin therapy is contraindicated in pregnancy. (E) Antiplatelet agents Consider aspirin therapy (75–162 mg/day) as a primary prevention strategy in those with type 1 or type 2 diabetes at increased cardiovascular risk (10-year risk >10%). This includes most men >50 years of age or women >60 years of age who have at least one additional major risk factor (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria). (C) Aspirin should not be recommended for CVD prevention for adults with diabetes at low CVD risk (10-year CVD risk 1.5 mg/dl), ARBs have been shown to delay the progression of nephropathy. (A) If one class is not tolerated, the other should be substituted. (E) Reduction of protein intake to 0.8–1.0 g · kg body wt–1 · day–1 in individuals with diabetes and the earlier stages of CKD and to 0.8 g · kg body wt–1 · day–1 in the later stages of CKD may improve measures of renal function (urine albumin excretion rate, GFR) and is recommended. (B) When ACE inhibitors, ARBs, or diuretics are used, monitor serum creatinine and potassium levels for the development of acute kidney disease and hyperkalemia. (E) Continued monitoring of urine albumin excretion to assess both response to therapy and progression of disease is recommended. (E) When estimated GFR (eGFR) is 130/80 mmHg, if 95% exceeds that value) should be initiated as soon as the diagnosis is confirmed. (E) ACE inhibitors should be considered for the initial treatment of hypertension, following appropriate reproductive counseling due to its potential teratogenic effects. (E) The goal of treatment is a blood pressure consistently 240 mg/dl) or a cardiovascular event before age 55 years, or if family history is unknown, then a fasting lipid profile should be performed on children >2 years of age soon after diagnosis (after glucose control has been established). If family history is not of concern, then the first lipid screening should be considered at puberty (≥10 years). All children diagnosed with diabetes at or after puberty should have a fasting lipid profile performed soon after diagnosis (after glucose control has been established). (E) For both age-groups, if lipids are abnormal, annual monitoring is recommended. If LDL cholesterol values are within the accepted risk levels ( 160 mg/dl (4.1 mmol/l), or LDL cholesterol >130 mg/dl (3.4 mmol/l) and one or more CVD risk factors, is reasonable. (E) The goal of therapy is an LDL cholesterol value <100 mg/dl (2.6 mmol/l). (E) Retinopathy The first ophthalmologic examination should be obtained once the child is ≥10 years of age and has had diabetes for 3–5 years. (E) After the initial examination, annual routine follow-up is generally recommended. Less frequent examinations may be acceptable on the advice of an eye care professional. (E) Celiac disease Children with type 1 diabetes should be screened for celiac disease by measuring tissue transglutaminase or anti-endomysial antibodies, with documentation of normal total serum IgA levels, soon after the diagnosis of diabetes. (E) Testing should be repeated in children with growth failure, failure to gain weight, weight loss, diarrhea, flatulence, abdominal pain, or signs of malabsorption or in children with frequent unexplained hypoglycemia or deterioration in glycemic control. (E) Children with positive antibodies should be referred to a gastroenterologist for evaluation with endoscopy and biopsy. (E) Children with biopsy-confirmed celiac disease should be placed on a gluten-free diet and have consultation with a dietitian experienced in managing both diabetes and celiac disease. (E) Hypothyroidism Children with type 1 diabetes should be screened for thyroid peroxidase and thyroglobulin antibodies at diagnosis. (E) TSH concentrations should be measured after metabolic control has been established. If normal, they should be rechecked every 1–2 years, or if the patient develops symptoms of thyroid dysfunction, thyromegaly, or an abnormal growth rate. (E) Preconception care A1C levels should be as close to normal as possible (<7%) in an individual patient before conception is attempted. (B) Starting at puberty, preconception counseling should be incorporated in the routine diabetes clinic visit for all women of child-bearing potential. (C) Women with diabetes who are contemplating pregnancy should be evaluated and, if indicated, treated for diabetic retinopathy, nephropathy, neuropathy, and CVD. (E) Medications used by such women should be evaluated prior to conception, since drugs commonly used to treat diabetes and its complications may be contraindicated or not recommended in pregnancy, including statins, ACE inhibitors, ARBs, and most non-insulin therapies. (E) Since many pregnancies are unplanned, consider the potential risks and benefits of medications that are contraindicated in pregnancy in all women of child-bearing potential, and counsel women using such medications accordingly. (E) Older adults Older adults who are functional, cognitively intact, and have significant life expectancy should receive diabetes care using goals developed for younger adults. (E) Glycemic goals for older adults not meeting the above criteria may be relaxed using individual criteria, but hyperglycemia leading to symptoms or risk of acute hyperglycemic complications should be avoided in all patients. (E) Other cardiovascular risk factors should be treated in older adults with consideration of the time frame of benefit and the individual patient. Treatment of hypertension is indicated in virtually all older adults, and lipid and aspirin therapy may benefit those with life expectancy at least equal to the time frame of primary or secondary prevention trials. (E) Screening for diabetes complications should be individualized in older adults, but particular attention should be paid to complications that would lead to functional impairment. (E) Diabetes care in the hospital All patients with diabetes admitted to the hospital should have their diabetes clearly identified in the medical record. (E) All patients with diabetes should have an order for blood glucose monitoring, with results available to all members of the health care team. (E) Goals for blood glucose levels: Critically ill patients: Insulin therapy should be initiated for treatment of persistent hyperglycemia starting at a threshold of no greater than 180 mg/dl (10 mmol/l). Once insulin therapy is started, a glucose range of 140–180 mg/dl (7.8 to 10 mmol/l) is recommended for the majority of critically ill patients. (A) More stringent goals, such as 110–140 mg/dl (6.1–7.8 mmol/l) may be appropriate for selected patients, as long as this can be achieved without significant hypoglycemia. (C) Critically ill patients require an intravenous insulin protocol that has demonstrated efficacy and safety in achieving the desired glucose range without increasing risk for severe hypoglycemia. (E) Non–critically ill patients: There is no clear evidence for specific blood glucose goals. If treated with insulin, the pre-meal blood glucose target should generally be <140 mg/dl (7.8 mmol/l) with random blood glucose <180 mg/dl (10.0 mmol/l), provided these targets can be safely achieved. More stringent targets may be appropriate in stable patients with previous tight glycemic control. Less stringent targets may be appropriate in those with severe comorbidites. (E) Scheduled subcutaneous insulin with basal, nutritional, and correction components is the preferred method for achieving and maintaining glucose control in non–critically ill patients. (C) Using correction dose or “supplemental” insulin to correct pre-meal hyperglycemia in addition to scheduled prandial and basal insulin is recommended. (E) Glucose monitoring should be initiated in any patient not known to be diabetic who receives therapy associated with high risk for hyperglycemia, including high-dose glucocorticoid therapy, initiation of enteral or parenteral nutrition, or other medications such as octreotide or immunosuppressive medications. (B) If hyperglycemia is documented and persistent, treatment is necessary. Such patients should be treated to the same glycemic goals as patients with known diabetes. (E) A hypoglycemia management protocol should be adopted and implemented by each hospital or hospital system. A plan for treating hypoglycemia should be established for each patient. Episodes of hypoglycemia in the hospital should be documented in the medial record and tracked. (E) All patients with diabetes admitted to the hospital should have an A1C obtained if the result of testing in the previous 2–3 months is not available. (E) Patients with hyperglycemia in the hospital who do not have a diagnosis of diabetes should have appropriate plans for follow-up testing and care documented at discharge. (E)

                Author and article information

                Diabetes Metab J
                Diabetes Metab J
                Diabetes & Metabolism Journal
                Korean Diabetes Association
                October 2013
                17 October 2013
                : 37
                : 5
                : 343-348
                [1 ]Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea.
                [2 ]Research Institute of Endocrinology, Kyung Hee University School of Medicine, Seoul, Korea.
                Author notes
                Corresponding author: Jeong-taek Woo. Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Korea. jtwoomd@
                Copyright © 2013 Korean Diabetes Association

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funded by: Ministry of Health and Welfare
                Award ID: A102065
                Original Article

                Endocrinology & Diabetes

                anemia, diabetes mellitus, diagnosis, hemoglobin a, glycosylated


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