Controversy: HbA1c vs blood glucose: what is the best option to diagnose Diabetes? Davide Carvalho Department of Endocrinology, Diabetes and Metabolism Centro Hospitalar S. João / University of Porto Medical School

A1c Why we need new tools to diagnose diabetes? Why A1c? Advantages of A1c versus FPG and OGTT Limitations of A1c What we don’t know in A1c for diagnosis

Prevalence of Diabetes In Portugal Gardete Correia L. First diabetes prevalence study in Portugal: PREVADIAB study. Diabet Med 2010; 27: Unknown diabetes Previously known

Gardete Correia L. First diabetes prevalence study in Portugal: PREVADIAB study. Diabet Med 2010; 27: Prevalence of Diabetes In Portugal Unknown diabetes Previously known Age groups At diagnosis, up to 25% of the patients had retinopathy – Harris MI et al Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis. Diabetes Care 1992;15:815-9.

Survey to Portuguese Physicians (most GP) that participated in a Pos-graduate course ( n=104) % % In the last month, in how many patients with glucose between 110 (6.1) and 126 mg/dl (6.9 mmol/L) did you perform an OGTT)? In how many of those pts with a glucose 2h pos load > 200mg/dL(11mmol/L), did you repeat the OGTT ?

A1c Why we need new tools to diagnose diabetes? Why A1c? Advantages of A1c versus FPG and OGTT Limitations of A1c What we don’t know in A1c for diagnosis

Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1999;22(Supp 1):S5-S19. FPG Glucose 2h P load HbA 1c Retinopathy (%) USA (NHANES III) FPG (mg/dL) GP2h (mg/dL) HbA 1c (%) Retinopathy in Adults with Unknown Diabetes Reasons to change the Diagnostic Criteria

Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1999;22(Supp 1):S5-S Retinopathy (%) FPG Glucose 2h P load HbA 1c Egypt FPG (mg/dL) GP2h (mg/dL) HbA 1c (%) Retinopathy in Adults with Unknown Diabetes Reasons to change the Diagnostic Criteria

Measurement of A1c Principle of all methods – Separate glycated an non-glycated forms – Differences in charges – HPLC – Differences in the structure – immunoassays or boronate affinity chromatography Standardization – National Glycohemoglobin Standardization Program (NGSP) – IFCC –An N-terminal hexapeptide is cleaved from the b-chain of hemoglobin by the enzyme endoproteinase Glu-C. HPLC separation and quantified separately by mass spectrometry or capillary electrophoresis; - Results 1.5-2% lower than NGSP

Bennett CM, et al. HbA1c as a screening tool for detection of type 2 diabetes: a systematic review.Diabet Med. 24, 333–343 (2007) A 1c – ≥ 6.1% threshold had a sensitivity between 78 and 81% and a specificity of 79 to 84%. FPG – a threshold of ≥ 110mg/dL (6.1 mmol/L), sensitivity varied from 48 to 64% and the specificity from 94 to 98%. Both A1c and FPG had lower sensitivity to detect IGT (around 50%).

Diabetes Prevalence using different criteria in 147 Morbid Obese Female patients ADA 2009 – Fasting Plasma Glucose ≥126mg/dL( 7.0 mmol/L); 2h Glucose after 75 g OGTT > 200mg/dL (11mmol/L); Random PG ≥200mg/dL + symptoms ADA 2010 – Fasting Plasma Glucose ≥126mg/dL (7.0mmol/L); 2h Glucose after 75g OGTT > 200mg/dL (11mmol/l); Random PG ≥200mg/dL + symptoms; A1c > 6.5% FPG ADA2010 ADA2009 A1c Glu2hOGTT 10.5% 18.5% 14% p=0.014 Mesquita J et al. Endocrine Abstracts 2011

HbA1c in diagnosing and predicting Type 2 diabetes in impaired glucose tolerance: the Finnish DiabetesPrevention Study Pajunen P. HbA1c in diagnosing and predicting Type 2 diabetes in impaired glucose tolerance: the Finnish Diabetes Prevention Study,. Diabet. Med 2011; 28: 36–42

Recommendations of the International Expert Committee For the diagnosis of diabetes: The HbA 1c assay is an accurate, precise measure of chronic glycaemic levels and correlates well with the risk of diabetes complications Diabetes should be diagnosed when HbA 1c is ≥6.5 %. Diagnosis should be confirmed with a repeat HbA 1c test. Confirmation is not required in symptomatic subjects with plasma glucose levels >200 mg/dl (>11.1 mmol/l) If HbA 1c testing is not possible, previously recommended diagnostic methods (e.g., FPG or 2hPG, with confirmation) are acceptable HbA 1c testing is indicated in children in whom diabetes is suspected but the classic symptoms and a casual plasma glucose >200 mg/dl (>11.1 mmol/l) are not found if two different tests (eg, FPG and A1C) are available and are concordant for the diagnosis of diabetes, additional testing is not needed. If two different tests are discordant, the test that is diagnostic of diabetes should be repeated to confirm the diagnosis

A1c Why we need new tools to diagnose diabetes? Why HbA1c? Advantages of A1c versus FPG and OGTT Limitations of A1c What we don’t know in A1c for diagnosis

– Close correlation between HbA1c and diabetic retinopathy – Improved instrumentation and standardization of HbA1c assay – Less biologic variability (<2%), greater preanalytic stability of HbA1c versus glucose tests (FPG, OGTT) - FPG – intraindividual variation – 6% - 2h pos load- variation 17% - More stable with time and temperature – No requirement for pretest fasting – The same test for diagnosis and monitoring (Broad familiarity with HbA1c in diabetes management) – Diagnostic criteria not followed (namely OGTT is not performed) – Not affected by short term lifestyle changes Advantages of A1c versus FPG and OGTT

A1c Why we need new tools to diagnose diabetes? Why HbA1c? Advantages of A1c versus FPG and OGTT Limitations of A1c What we don’t know in A1c for diagnosis

– Small number of studies – More expensive than FPG – Limited availability in some areas of the World – Normal threshold not clearly established Limitations of A1c for screen and diagnosis

Precautions Using A1c Any condition that ↓ mean erythrocyte age, will lower A1c test results – hemolytic anemia or recovery from acute blood loss Any condition that ↑ erythrocyte age, will increase A1c test results – Splenectomy, aplastic anemia Structural hemoglobinopathies and thalassemia syndromes may alter A1c – The HbS trait which affects approximately 8% of African; – HbC trait, which affects approximately 3% of African – HbE trait, which affects approximately 10% Asian – Hb F, associated with talassemia may affect some A1c assays Environmental factors, including uremia, hyperbilirubinemia, hyper- triglyceridemia, chronic alcoholism, chronic ingestion of salicylates, vitamin C ingestion, and opiate addiction, can falsely increase HbA1c Vitamin C and vitamin E ingestion may been reported to falsely lower A1c. National Glycohemoglobin Standardization Program. Factors that interfere with GHB (HbA1c) test results. 2009

A1c Why we need new tools to diagnose diabetes? Why A1c? Advantages of A1c versus FPG and OGTT Limitations of A1c What we don’t know in A1c for diagnosis

Recommendations of the International Expert Committee For the identification of those at high risk for diabetes: The risk for diabetes based on levels of glycaemia is a continuum; therefore, there is no lower glycaemic threshold at which risk clearly begins The categorical clinical states prediabetes, IFG, and IGT fail to capture the continuum of risk and will be phased out of use as HbA 1c measurements replace glucose measurements As for the diagnosis of diabetes, the A 1c assay has several advantages over laboratory measures of glucose in identifying individuals at high risk for developing diabetes Those with HbA 1c levels below the threshold for diabetes but ≥6.0 % ( ADA %) should receive demonstrably effective preventive interventions. Those with HbA 1c below this range may still be at risk and, depending on the presence of other risk factors, may also benefit from prevention efforts The HbA 1c level at which population-based prevention services begin should be based on the nature of the intervention, the resources available, and the size of the affected population

A1c as preditor of diabetes 12,375 patients, observed between Jan 2000 and Dec 2001, performed several A1c measurements During the follow-up 4.4 years, 3,329 (26,9%) develop diabetes Cheng P. HemoglobinA1c as a Predictor of Incident Diabetes. Diabetes Care 2011

Risk of Developing Diabetes Mellitus Cheng P. HemoglobinA1c asaPredictor of Incident Diabetes. Diabetes Care 2011

Probability of having diabetes according to A 1 c basal levels Months of follow-up Probability of a Diabetes event Cheng P. HemoglobinA1c as a Predictor of Incident Diabetes. Diabetes Care 2011

Conclusions A1c for diabetes diagnosis offers greater convenience and accuracy than glucose measurements and correlates well with long-term complications Diabetes should be diagnosed when A1c is ≥6.5 %. If HbA1c testing is not possible, previously recommended diagnostic methods are acceptable A value > 5.7 and < 6.4 – is diagnostic of intermediate hyperglycemia