Editing Glycated hemoglobin

{{Short description|Form of hemoglobin chemically linked to a sugar}}
{{redirect|A1C}}
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'''Glycated hemoglobin''', also called '''glycohemoglobin''', is a form of [[hemoglobin]] (Hb) that is chemically linked to a sugar.{{NoteTag|"Glycosylated haemoglobin" is a common misnomer because glycation and glycosylation are different processes, of which only the former is relevant in this case. Glycation is a non-enzymatic process, while glycosylation is enzymatic.}} Most [[monosaccharide]]s, including [[glucose]], [[galactose]], and [[fructose]], spontaneously (that is, [[enzyme|non-enzymatically]]) bond with hemoglobin when they are present in the bloodstream. However, glucose is only 21% as likely to do so as galactose and 13% as likely to do so as fructose, which may explain why glucose is used as the primary metabolic fuel in humans.<ref name="pmid12192669">{{cite journal |vauthors=Bunn HF, Higgins PJ |title=Reaction of monosaccharides with proteins: possible evolutionary significance |journal=Science |volume=213 |issue=4504 |pages=222–4 |date=July 1981 |bibcode=1981Sci...213..222B |pmid=12192669 |doi=10.1126/science.12192669}}</ref><ref>{{cite journal |vauthors=McPherson JD, Shilton BH, Walton DJ |title=Role of fructose in glycation and cross-linking of proteins |journal=Biochemistry |volume=27 |issue=6 |pages=1901–7 |date=March 1988 |pmid=3132203 |doi=10.1021/bi00406a016}}</ref>

The formation of excess sugar-hemoglobin linkages indicates the presence of excessive sugar in the bloodstream and is an indicator of [[diabetes]] or other hormone diseases in high concentration {{Nowrap|(HbA1c > 6.4%)}}.<ref>{{cite journal |last=Pongudom |first=Saranya |date=1 November 2019 |title=Determination of Normal HbA1C Levels in Non-Diabetic Patients with Hemoglobin E |journal=[[Annals of Clinical & Laboratory Science]] |volume=49 |issue=6 |pages=804–9 |pmid=31882432 |url=http://www.annclinlabsci.org/content/49/6/804.long}}</ref> A1c is of particular interest because it is easy to detect. The process by which sugars attach to hemoglobin is called [[glycation]] and the reference system is based on HbA1c, defined as beta-N-1-deoxy fructosyl hemoglobin as component.<ref name="pmid16112961">{{cite journal |author=Miedema K |title=Standardization of HbA1c and Optimal Range of Monitoring |journal=Scandinavian Journal of Clinical and Laboratory Investigation |volume=240 |year=2005 |pages=61–72 |pmid=16112961 |doi=10.1080/00365510500236143 |s2cid=30162967}}</ref>

There are several ways to measure glycated hemoglobin, of which '''HbA1c''' (or simply '''A1c''') is a standard single test.<ref name="umich">Elizabeth Weiser Caswell Diabetes Institute. [https://diabetes.med.umich.edu/about/resources-health-professionals/hemoglobin-a1c-fact-sheet Hemoglobin A1c Fact Sheet]. Accessed 2024-07-02.</ref> HbA1c is measured primarily to determine the three-month average [[blood sugar level]] and is used as a standard diagnostic test for evaluating the risk of complications of [[diabetes]] and as an assessment of [[glycemic control]].<ref name=umich/><ref>{{cite book |chapter=2. Glycated haemoglobin (HbA1c) for the diagnosis of diabetes |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK304271/ |id=NBK304271 |editor= |title=Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus: Abbreviated Report of a WHO Consultation |series=WHO Guidelines Approved by the Guidelines Review Committee |publisher=World Health Organization |date=2011 |pmid=26158184 |url=https://www.ncbi.nlm.nih.gov/books/NBK304267/}}</ref> The test is considered a three-month average because the average lifespan of a red blood cell is three to four months. Normal levels of glucose produce a normal amount of glycated hemoglobin. As the average amount of plasma glucose increases, the fraction of glycated hemoglobin increases in a predictable way. In diabetes, higher amounts of glycated hemoglobin, indicating higher blood glucose levels, have been associated with [[cardiovascular disease]], [[nephropathy]], [[neuropathy]], and [[retinopathy]].<ref name="pmid28760792" />

==Terminology==
[[Glycation|Glycated]] hemoglobin is preferred over [[glycosylation|glycosylated]] hemoglobin to reflect the correct (non-enzymatic) process. Early literature often used ''glycosylated'' as it was unclear which process was involved until further research was performed. The terms are still sometimes used interchangeably in English-language literature.<ref>{{cite journal
|title=Glycated or glycosylated?
|author=Oliwia Witczak, Trine B. Haugen
|date=25 November 2014
|journal=[[Journal of the Norwegian Medical Association]]
|volume=134
|issue=22
|pages=2179
|pmid=25423986
|doi=10.4045/tidsskr.14.0172
|doi-access=free
|url=https://tidsskriftet.no/en/2014/11/glycated-or-glycosylated
|access-date=5 December 2018
|url-status=live
|archive-url=https://web.archive.org/web/20181205145806/https://tidsskriftet.no/en/2014/11/glycated-or-glycosylated
|archive-date=5 December 2018
|quote=Hospitals should ensure that the correct term for HbA1c — glycated haemoglobin — is now to be found in laboratory manuals.
}}</ref>

The naming of HbA1c derives from hemoglobin type A being separated on [[ion chromatography|cation exchange chromatography]]. The first fraction to separate, probably considered to be pure hemoglobin A, was designated HbA0, and the following fractions were designated HbA1a, HbA1b, and HbA1c, in their order of [[elution]]. Improved separation techniques have subsequently led to the isolation of more [[wikt:subfraction|subfraction]]s.<ref name="pmid9732983">{{cite journal |vauthors=Peterson KP, Pavlovich JG, Goldstein D, Little R, England J, Peterson CM |title=What is hemoglobin A1c? An analysis of glycated hemoglobins by electrospray ionization mass spectrometry |journal=[[Clinical Chemistry (journal)|Clinical Chemistry]] |volume=44 |issue=9 |year=1998 |pages=1951–8 |pmid=9732983 |doi=10.1093/clinchem/44.9.1951 |doi-access=free |url=https://academic.oup.com/clinchem/article/44/9/1951/5642934 |access-date=2024-06-21 |url-status=live |archive-url=https://web.archive.org/web/20150923223202/http://www.clinchem.org/content/44/9/1951.long |archive-date=2015-09-23}}</ref>

==History==
Hemoglobin A1c was first separated from other forms of hemoglobin by Huisman and Meyering in 1958 using a [[chromatography|chromatographic column]].<ref>{{cite journal |vauthors=Huisman TH, Martis EA, Dozy A |title=Chromatography of hemoglobin types on carboxymethylcellulose |journal=J. Lab. Clin. Med. |volume=52 |issue=2 |pages=312–327 |year=1958 |pmid=13564011}}</ref> It was first characterized as a [[glycoprotein]] by Bookchin and Gallop in 1968.<ref name="pmid4874776">{{cite journal |vauthors=Bookchin RM, Gallop PM |title=Structure of haemoglobin A1c: nature of the N-terminal beta chain blocking group |journal=Biochem. Biophys. Res. Commun. |volume=32 |issue=1 |pages=86–93 |year=1968 |pmid=4874776 |doi=10.1016/0006-291X(68)90430-0}}</ref> Its increase in diabetes was first described in 1969 by [[Samuel Rahbar]] ''[[et al]].''<ref name="pmid5808299">{{cite journal |vauthors=Rahbar S, Blumenfeld O, Ranney HM |title=Studies of an unusual hemoglobin in patients with diabetes mellitus |journal=Biochem. Biophys. Res. Commun. |volume=36 |issue=5 |pages=838–843 |year=1969 |pmid=5808299 |doi=10.1016/0006-291X(69)90685-8}}</ref> The reactions leading to its formation were characterized by Bunn and his coworkers in 1975.<ref name="pmid1201013">{{cite journal |vauthors=Bunn HF, Haney DN, Gabbay KH, Gallop PM |title=Further identification of the nature and linkage of the carbohydrate in haemoglobin A1c |journal=Biochem. Biophys. Res. Commun. |volume=67 |issue=1 |pages=103–9 |year=1975 |pmid=1201013 |doi=10.1016/0006-291X(75)90289-2}}</ref>

The use of hemoglobin A1c for monitoring the degree of control of glucose metabolism in diabetic patients was proposed in 1976 by [[Anthony Cerami]], Ronald Koenig, and coworkers.<ref name="pmid934240">{{cite journal |vauthors=Koenig RJ, Peterson CM, Jones RL, Saudek C, Lehrman M, Cerami A |title=Correlation of glucose regulation and hemoglobin AIc in diabetes mellitus |journal=N. Engl. J. Med. |volume=295 |issue=8 |pages=417–420 |year=1976 |pmid=934240 |doi=10.1056/NEJM197608192950804}}</ref>

==Damage mechanisms==
Glycated hemoglobin causes an increase of highly reactive [[radical (chemistry)|free radicals]] inside blood cells, altering the properties of their [[cell membrane]]s. This leads to [[erythrocyte aggregation|blood cell aggregation]] and increased blood [[viscosity]], which results in impaired blood flow.<ref name=":0">{{cite journal |last=Saleh |first=Jumana |date=2015-08-26 |title=Glycated hemoglobin and its spinoffs: Cardiovascular disease markers or risk factors? |journal=World Journal of Cardiology |volume=7 |issue=8 |pages=449–453 |pmid=26322184 |doi=10.4330/wjc.v7.i8.449 |doi-access=free |pmc=4549778}}</ref>

Another way glycated hemoglobin causes damage is via [[inflammation]], which results in [[atherosclerosis|atherosclerotic]] plaque ([[atheroma]]) formation. Free-radical build-up promotes the [[excited state|excitation]] of [[Ferrous|Fe<sup>2+</sup>]]-hemoglobin through {{nobr|[[ferric|Fe<sup>3+</sup>]]-Hb}} into abnormal [[ferryl]] hemoglobin (Fe<sup>4+</sup>-Hb). Fe<sup>4+</sup> is unstable and reacts with specific [[amino acid]]s in hemoglobin to regain its Fe<sup>3+</sup> [[oxidation state]]. Hemoglobin molecules clump together via [[cross-link|cross-linking reactions]], and these hemoglobin clumps (multimers) promote cell damage and the release of Fe<sup>4+</sup>-hemoglobin into the [[extracellular matrix|matrix]] of innermost layers ([[tunica intima|subendothelium]]) of arteries and veins. This results in increased permeability of interior surface ([[endothelium]]) of blood vessels and production of pro-inflammatory [[monocyte]] [[adhesion]] proteins, which promote [[macrophage]] accumulation in blood vessel surfaces, ultimately leading to harmful plaques in these vessels.<ref name=":0"/>

Highly glycated Hb-[[advanced glycation end-product|AGEs]] go through [[vascular smooth muscle]] layer and inactivate [[acetylcholine]]-induced endothelium-dependent relaxation, possibly through binding to [[nitric oxide]] (NO), preventing its normal function. NO is a potent [[vasodilation|vasodilator]] and also inhibits formation of plaque-promoting [[low-density lipoprotein|LDLs]] (sometimes called "bad cholesterol") [[redox|oxidized]] form.<ref name=":0"/>

This overall degradation of blood cells also releases [[heme]] from them. Loose heme can cause oxidation of endothelial and LDL proteins, which results in plaques.<ref name=":0"/>

[[File:GlycationViaAmadoriRgmt.svg|thumb|364px|Glycation pathway via Amadori rearrangement (in HbA1c, R is typically N-terminal valine).<ref>{{cite journal |title=Chemistry of Amadori Rearrangement Products: Analysis, Synthesis, Kinetics, Reactions, and Spectroscopic Properties |author1=Yaylayan, Varoujan A. |author2=Huyghues-Despointes, Alexis |journal=Critical Reviews in Food Science and Nutrition |year=1994 |volume=34 |issue=4 |pages=321–369 |pmid=7945894 |doi=10.1080/10408399409527667}}</ref>]]

==Principle in medical diagnostics==
Glycation of proteins is a frequent occurrence, but in the case of hemoglobin, a nonenzymatic condensation reaction occurs between glucose and the N-end of the [[beta chain]]. This reaction produces a [[Schiff base]] ({{chem2|R\sN\dCHR'}}, R=beta chain, CHR'=glucose-derived), which is itself converted to 1-deoxyfructose. This second conversion is an example of an [[Amadori rearrangement]].{{cn|date=September 2024}}

When blood glucose levels are high, [[glucose]] molecules attach to the hemoglobin in [[red blood cell]]s. The longer hyperglycemia occurs in blood, the more glucose binds to hemoglobin in the red blood cells and the higher the glycated hemoglobin.<ref name="pmid33806493">{{cite journal |vauthors=Pohanka M |title=Glycated Hemoglobin and Methods for Its Point of Care Testing |journal=Biosensors |volume=11 |issue=3 |date=March 2021 |page=70 |pmid=33806493 |doi=10.3390/bios11030070 |doi-access=free |pmc=8000313}}</ref>

Once a hemoglobin molecule is glycated, it remains that way. A buildup of glycated hemoglobin within the red cell, therefore, reflects the average level of glucose to which the cell has been exposed during its [[red blood cell#Life cycle|life-cycle]]. Measuring glycated hemoglobin assesses the effectiveness of therapy by monitoring long-term serum glucose regulation.

A1c is a weighted average of blood glucose levels during the life of the red blood cells (117 days for men and 106 days in women<ref>{{cite journal |last=Unnikrishnan |first=Ranjit |date=Jul–Aug 2012 |title=Drugs affecting HbA1c levels |journal=Indian Journal of Endocrinology and Metabolism |volume=16 |issue=4 |pages=528–531 |pmid=22837911 |doi=10.4103/2230-8210.98004 |doi-access=free |pmc=3401751}}</ref>). Therefore, glucose levels on days nearer to the test contribute substantially more to the level of A1c than the levels in days further from the test.<ref>{{cite web |title=NGSP: HbA1c and eAG |website=ngsp.org |url=https://ngsp.org/A1ceAG.asp |access-date=2024-06-21 |url-status=live |archive-url=https://web.archive.org/web/20151015124504/http://www.ngsp.org/A1ceAG.asp |archive-date=2015-10-15}}</ref>

This is also supported by data from clinical practice showing that HbA1c levels improved significantly after 20 days from start or intensification of glucose-lowering treatment.<ref>{{cite journal |vauthors=Sidorenkov G, Haaijer-Ruskamp FM, de Zeeuw D, Denig P |title=A longitudinal study examining adherence to guidelines in diabetes care according to different definitions of adequacy and timeliness |journal=PLOS ONE |volume=6 |issue=9 |pages=e24278 |year=2011 |bibcode=2011PLoSO...624278S |pmid=21931669 |doi=10.1371/journal.pone.0024278 |doi-access=free |pmc=3169586}}</ref>

==Measurement==
Several techniques are used to measure hemoglobin A1c. Laboratories may use [[high-performance liquid chromatography]], [[immunoassay]], [[enzymatic]] assay, [[capillary electrophoresis]], or [[boronate affinity chromatography]]. [[Point of care]] (e.g., doctor's office) devices use immunoassay boronate affinity chromatography.<ref name="pmid33806493"/>

In the United States, HbA<sub>1c</sub> testing laboratories are certified by the National Glycohemoglobin Standardization Program to standardize them against the results of the 1993 [[Diabetes Control and Complications Trial]] (DCCT).<ref>[http://www.devicelink.com/ivdt/archive/08/07/009.html Developing Point of care HbA1c tests for Diabetes monitoring] {{Webarchive|url=https://web.archive.org/web/20080829202705/http://www.devicelink.com/ivdt/archive/08/07/009.html |date=2008-08-29}}, Barry Plant, Originally Published IVDT July/August 2008</ref> An additional percentage scale, Mono S has previously been in use by Sweden and KO500 is in use in Japan.<ref>[Clinical Chemistry 50:1 166–174 (2004)]</ref><ref name=SDA>[http://www.hba1c.nu/HbA1c_Equalis-en.pdf HbA1c in a new way] {{Webarchive|url=https://web.archive.org/web/20130909224716/http://hba1c.nu/HbA1c_Equalis-en.pdf |date=2013-09-09}} By the Swedish Diabetes Association. Retrieved 2023-02-01.</ref>

===Switch to IFCC units===
The American Diabetes Association, [[European Association for the Study of Diabetes]], and [[International Diabetes Federation]] have agreed that, in the future, HbA<sub>1c</sub> is to be reported in the [[International Federation of Clinical Chemistry and Laboratory Medicine]] (IFCC) units.<ref name="pmid18539643">{{cite journal |vauthors=Geistanger A, Arends S, Berding C, Hoshino T, Jeppsson JO, Little R, Siebelder C, Weykamp C |title=Statistical methods for monitoring the relationship between the IFCC reference measurement procedure for hemoglobin A1c and the designated comparison methods in the United States, Japan, and Sweden |journal=Clin. Chem. |volume=54 |issue=8 |pages=1379–85 |date=August 2008 |pmid=18539643 |doi=10.1373/clinchem.2008.103556 |doi-access=free}}</ref> IFCC reporting was introduced in Europe except for the UK in 2003;<ref name="pmid15209757">{{cite journal |vauthors=Manley S, John WG, Marshall S |title=Introduction of IFCC reference method for calibration of HbA: implications for clinical care |journal=Diabet. Med. |volume=21 |issue=7 |pages=673–6 |date=July 2004 |pmid=15209757 |doi=10.1111/j.1464-5491.2004.01311.x |s2cid=30468208}}</ref> the UK carried out dual reporting from 1 June 2009 <ref>{{cite press release |title=Standardisation of the reference method for the measurement of HbA1c to improve diabetes care |date=April 2008 |publisher=[[Association for Clinical Biochemistry and Laboratory Medicine]] (with [[Diabetes UK]]) |url=http://www.acb.org.uk/docs/hba1c.pdf |access-date=2009-07-02 |url-status=dead |archive-url=https://web.archive.org/web/20110722031224/http://www.acb.org.uk/docs/hba1c.pdf |archive-date=2011-07-22}}</ref> until 1 October 2011.

Conversion between DCCT and IFCC is by the following equation:<ref name="DiabetesUK conversion">{{cite web |title=HbA1c Standardisation For Laboratory Professionals |publisher=[[Diabetes UK]] (with [[Association for Clinical Biochemistry and Laboratory Medicine]]) |url=https://www.diabetes.org.uk/resources-s3/2017-11/53130hba1chcpleaflet.pdf |access-date=2009-07-02 |url-status=live |archive-url=https://web.archive.org/web/20110720104405/http://www.diabetes.org.uk/upload/Professionals/Key%20leaflets/53130HbA1cLableaflet.pdf |archive-date=2011-07-20}}</ref>

:<math> \mathrm{IFCC\ HBA1c}\, \Big(\frac{\text{mmol}}{\text{mol}}\Big)=[\mathrm{DCCT\ HBA1c}\,(\%) - 2.14] \times 10.929 </math>

{| class="wikitable collapsible collapsed"
!"IFCC" HbA<sub>1c</sub> || "DCCT" HbA<sub>1c</sub> || "Mono S" HbA<sub>1c</sub><ref name=SDA/>
|-
| (mmol/mol) || (%) || (%)
|-
| 10 || 3.1 || 2.0
|-
| 20 || 4.0 || 2.9
|-
| 30 || 4.9 || 3.9
|-
| 40 || 5.8 || 4.8
|-
| 45 || 6.3 || 5.3
|-
| 50 || 6.7 || 5.8
|-
| 55 || 7.2 || 6.3
|-
| 60 || 7.6 || 6.8
|-
| 65 || 8.1 || 7.2
|-
| 70 || 8.6 || 7.7
|-
| 80 || 9.5 || 8.7
|-
| 90 || 10.4 || 9.6
|-
| 100|| 11.3 || 10.6
|}

==Interpretation of results==
Laboratory results may differ depending on the analytical technique, the age of the subject, and biological variation among individuals. Higher levels of HbA<sub>1c</sub> are found in people with persistently elevated blood sugar, as in [[diabetes mellitus]]. While diabetic patient treatment goals vary, many include a target range of HbA<sub>1c</sub> values. A diabetic person with good glucose control has an HbA<sub>1c</sub> level that is close to or within the reference range.{{citation needed|date=July 2020}}

The International Diabetes Federation and the American College of Endocrinology recommend HbA<sub>1c</sub> values below 48&nbsp;mmol/mol (6.5 DCCT %), while the [[American Diabetes Association]] recommends HbA<sub>1c</sub> be below 53&nbsp;mmol/mol (7.0 DCCT %) for most patients.<ref>{{cite journal |title=Executive Summary: Standards of medical care in diabetes — 2009 |journal=Diabetes Care |volume=32 |pages=S6–S12 |year=2009 |issue=Suppl 1 |pmid=19118288 |doi=10.2337/dc09-S006 |pmc=2613586}}</ref> Results from large trials in {{nowrap|2008–09}} suggested that a target below 53&nbsp;mmol/mol (7.0 DCCT %) for older adults with type 2 diabetes may be excessive: Below 53&nbsp;mmol/mol, the health benefits of reduced A1c become smaller, and the intensive glycemic control required to reach this level leads to an increased rate of dangerous hypoglycemic episodes.<ref>{{cite journal |vauthors=Lehman R, Krumholz HM |title=Tight control of blood glucose in long standing type 2 diabetes |journal=Br Med J |year=2009 |volume=338 |page=b800 |pmid=19264821 |doi=10.1136/bmj.b800 |s2cid=45188963}}</ref>

A retrospective study of 47,970 type 2 diabetes patients, aged 50 years and older, found that patients with an HbA<sub>1c</sub> more than 48&nbsp;mmol/mol (6.5 DCCT %) had an increased mortality rate,<ref>{{cite journal |volume=375 |issue=9713 |title=Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study |journal=The Lancet |pages=481–9 |year=2010 |last1=Currie |first1=Craig J |last2=Peters |first2=John R |last3=Tynan |first3=Aodán |last4=Evans |first4=Marc |last5=Heine |first5=Robert J |last6=Bracco |first6=Oswaldo L |last7=Zagar |first7=Tony |last8=Poole |first8=Chris D |pmid=20110121 |doi=10.1016/S0140-6736(09)61969-3 |s2cid=21223855}}</ref> but a later international study contradicted these findings.<ref>{{cite web |title=Advance Study Contradicts ACCORD Findings |publisher=Diabetes Self-Management |date=2008-03-07 |url=http://www.diabetesselfmanagement.com/Blog/Tara-Dairman/advance_study_contradicts_accord_findings/ |access-date=2013-06-10 |url-status=dead |archive-url=https://web.archive.org/web/20120717105920/http://www.diabetesselfmanagement.com/Blog/Tara-Dairman/advance_study_contradicts_accord_findings/ |archive-date=2012-07-17}}</ref><ref>{{cite journal |vauthors=((ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F)) |title=Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes |journal=N Engl J Med |volume=358 |issue=24 |pages=2560–72 |date=June 2008 |pmid=18539916 |doi=10.1056/NEJMoa0802987 |quote=Conclusions: A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy|hdl=10072/26242 |hdl-access=free }} ({{ClinicalTrialsGov|NCT00145925|Blood Pressure and Glucose Lowering for the Prevention of Vascular Disease in High Risk Patients With Type 2 Diabetes}})</ref><ref>{{cite journal |title=A Summary of the Advance Trial |journal=Diabetes Care |date=2009-11-01 |pages=S357–61 |volume=32 |issue=Suppl 2 |last=Heller |first=Simon R. |pmid=19875581 |doi=10.2337/dc09-S339 |pmc=2811451}}</ref>

A review of the [[UKPDS]], Action to Control Cardiovascular Risk in Diabetes (ACCORD), Advance and Veterans Affairs Diabetes Trials (VADT) estimated that the risks of the main complications of diabetes ([[diabetic retinopathy]], [[diabetic nephropathy]], [[diabetic neuropathy]], and [[macrovascular disease]]) decreased by about 3% for every 1&nbsp;mmol/mol decrease in HbA<sub>1c</sub>.<ref>{{cite journal |vauthors=Shubrook JH, Shubrook J |title=Risks and benefits of attaining HbA(1c) goals: Examining the evidence |journal=The Journal of the American Osteopathic Association |volume=110 |issue=7 Suppl 7 |pages=e7–e12 |year=2010 |pmid=20644204}}</ref>

However, a trial by ACCORD designed specifically to determine whether reducing HbA<sub>1c</sub> below 42&nbsp;mmol/mol (6.0 DCCT %) using increased amounts of medication would reduce the rate of cardiovascular events found higher mortality with this intensive therapy, so much so that the trial was terminated 17 months early.<ref name=accord2008>{{cite journal |title=Effects of Intensive Glucose Lowering in Type 2 Diabetes |journal=New England Journal of Medicine |volume=358 |issue=24 |year=2008 |pages=2545–59 |vauthors=Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT |display-authors=3 |pmid=18539917 |doi=10.1056/NEJMoa0802743 |doi-access=free |pmc=4551392}}</ref>

Practitioners must consider patients' health, their risk of hypoglycemia, and their specific health risks when setting a target HbA<sub>1c</sub> level. Because patients are responsible for averting or responding to their own hypoglycemic episodes, their input and the doctors' assessments of the patients' [[self-care]] skills are also important.{{cn|date=September 2024}}

Persistent elevations in blood sugar (and, therefore, HbA<sub>1c</sub>) increase the risk of long-term vascular complications of diabetes, such as [[coronary disease]], [[heart attack]], [[stroke]], [[heart failure]], [[chronic kidney disease|kidney failure]], [[blindness]], [[erectile dysfunction]], [[neuropathy]] (loss of sensation, especially in the feet), [[gangrene]], and [[gastroparesis]] (slowed emptying of the stomach). Poor blood glucose control also increases the risk of short-term complications of surgery such as poor [[wound healing]].{{cn|date=September 2024}}

[[Mortality rate|All-cause mortality]] is higher above 64&nbsp;mmol/mol (8.0 DCCT%) HbA1c as well as below 42&nbsp;mmol/mol (6.0 DCCT %) in diabetic patients, and above 42&nbsp;mmol/mol (6.0 DCCT %) as well as below 31&nbsp;mmol/mol (5.0 DCCT %) in non-diabetic persons, indicating the risks of [[hyperglycemia]] and [[hypoglycemia]], respectively.<ref name="pmid28760792">{{cite journal |vauthors=Cavero-Redondo I, Peleteiro B, Martínez-Vizcaíno V |title=Glycated haemoglobin A1c as a risk factor of cardiovascular outcomes and all-cause mortality in diabetic and non-diabetic populations: a systematic review and meta-analysis |journal=[[BMJ Open]] |volume=7 |issue=7 |pages=e015949 |year=2017 |pmid=28760792 |doi=10.1136/bmjopen-2017-015949 |pmc=5642750}}</ref> Similar risk results are seen for [[cardiovascular disease]].<ref name="pmid28760792"/>

The 2022 ADA guidelines reaffirmed the recommendation that HbA1c should be maintained below 7.0% for most patients. Higher target values are appropriate for children and adolescents, patients with extensive co-morbid illness and those with a history of severe hypoglycemia.  More stringent targets (<6.0%) are preferred for pregnant patients if this can be achieved without significant hypoglycemia.<ref name="2022 ADA Guidelines" />

=== Factors other than glucose that affect A1c ===
Lower-than-expected levels of HbA<sub>1c</sub> can be seen in people with shortened red blood cell lifespans, such as with [[glucose-6-phosphate dehydrogenase deficiency]], [[sickle-cell disease]], or any other condition causing premature red blood cell death. For these patients, alternate assessment with [[fructosamine]] or glycated [[albumin]] is recommended; these methods reflect glycemic control over the preceding 2-3 weeks.<ref name="Sacks" /> Blood donation will result in rapid replacement of lost RBCs with newly formed red blood cells. Since these new RBCs will have only existed for a short period of time, their presence will lead HbA<sub>1c</sub> to underestimate the actual average levels. There may also be distortions resulting from [[blood donation]] during the preceding two months, due to an abnormal synchronization of the age of the RBCs, resulting in an older than normal average blood cell life (resulting in an overestimate of actual average blood glucose levels). Conversely, higher-than-expected levels can be seen in people with a longer red blood cell lifespan, such as with iron deficiency.<ref name="Kilpatrick 2009">{{cite journal |title=Is haemoglobin A1c a step forward for diagnosing diabetes? |vauthors=Kilpatrick ES, Bloomgarden ZT, Zimmet PZ |journal=BMJ |year=2009 |volume=339 |pages=b4432 |pmid=19903702 |doi=10.1136/bmj.b4432 |s2cid=36941786}}</ref>

Results can be unreliable in many circumstances, for example after blood loss, after surgery, blood transfusions, anemia, or high erythrocyte turnover; in the presence of chronic renal or liver disease; after administration of high-dose vitamin C; or [[erythropoetin]] treatment.<ref name="pmid18540046">{{cite journal |vauthors=Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ |title=Translating the A1C assay into estimated average glucose values. |journal=Diabetes Care |volume=31 |issue=8 |pages=1473–8 |year=2008 |pmid=18540046 |doi=10.2337/dc08-0545 |pmc=2742903 |url=https://diabetesjournals.org/care/article/31/8/1473/28589/Translating-the-A1C-Assay-Into-Estimated-Average |access-date=2009-09-24 |url-status=live |archive-url=https://web.archive.org/web/20120219165011/http://care.diabetesjournals.org/content/31/8/1473.full |archive-date=2012-02-19}}</ref> [[Hypothyroidism]] can artificially raise the A1c.<ref>{{cite web |date=12 November 2010 |title=Hypothyroidism Falsely Raises HbA1c and Glycated Albumin Levels |website=Diabetes In Control |url=http://www.diabetesincontrol.com/articles/diabetes-news/10065-hypothyroidism-falsely-raises-hba1c-and-glycated-albumin-levels |access-date=6 August 2015 |url-status=dead |archive-url=https://web.archive.org/web/20150923214243/http://www.diabetesincontrol.com/articles/diabetes-news/10065-hypothyroidism-falsely-raises-hba1c-and-glycated-albumin-levels |archive-date=23 September 2015}}</ref><ref>{{cite journal |date=7 September 2010 |title=Effects of Thyroid Hormone on A1C and Glycated Albumin Levels in Nondiabetic Subjects With Overt Hypothyroidism |last1=Kim |first1=M. K. |last2=Kwon |first2=H. S. |last3=Baek |first3=K. H. |last4=Lee |first4=J. H. |last5=Park |first5=W. C. |last6=Sohn |first6=H. S. |last7=Lee |first7=K. W. |last8=Song |first8=K. H. |journal=Diabetes Care |volume=33 |issue=12 |pages=2546–8 |pmid=20823345 |doi=10.2337/dc10-0988 |doi-access=free |pmc=2992186}}</ref><ref>{{cite journal |vauthors=Bhattacharjee R, Thukral A, Chakraborty PP, Roy A, Goswami S, Ghosh S, Mukhopadhyay P, Mukhopadhyay S, Chowdhury S |title=Effects of thyroid status on glycated hemoglobin |journal=Indian J Endocrinol Metab |volume=21 |issue=1 |pages=26–30 |date=2017 |pmid=28217494 |pmc=5240076 |doi=10.4103/2230-8210.196017 |doi-access=free}}</ref> In general, the [[reference range]] (that found in healthy young persons), is about 30–33&nbsp;mmol/mol (4.9–5.2 DCCT %).<ref>{{cite journal |title=Distribution of HbA(1c) levels for children and young adults in the U.S.: Third National Health and Nutrition Examination Survey |journal=Diabetes Care |date=2002-08-01 |issn=0149-5992 |pages=1326–30 |volume=25 |issue=8 |last1=Saaddine |first1=Jinan B. |last2=Fagot-Campagna |first2=Anne |last3=Rolka |first3=Deborah |last4=Narayan |first4=K. M. Venkat |last5=Geiss |first5=Linda |last6=Eberhardt |first6=Mark |last7=Flegal |first7=Katherine M. |pmid=12145229 |doi=10.2337/diacare.25.8.1326 |doi-access=free}}</ref> The mean HbA<sub>1c</sub> for diabetics type 1 in Sweden in 2014 was 63&nbsp;mmol/mol (7.9 DCCT%) and for type 2, 61&nbsp;mmol/mol (7.7 DCCT%).<ref>{{cite web |title=Nationella Diabetesregistret Årsrapport 2014 års resultat |website=Nationella Diabetesregistret Årsrapport 2014 års resultat |publisher=Nationella Diabetes Registret |language=sv |url=https://www.ndr.nu/pdfs/Arsrapport_NDR_2014.pdf |access-date=2015-12-14 |url-status=live |archive-url=https://web.archive.org/web/20171002215923/https://www.ndr.nu/pdfs/Arsrapport_NDR_2014.pdf |archive-date=2017-10-02}}</ref> HbA1c levels show a small, but statistically significant, progressive uptick with age; the clinical importance of this increase is unclear.<ref name="Sacks" />

=== Mapping from A1c to estimated average glucose ===
The approximate mapping between HbA<sub>1c</sub> values given in DCCT percentage (%) and eAG (estimated average glucose) measurements is given by the following equation:<ref name="pmid18540046"/>
:eAG(mg/dL) = 28.7 × A1C − 46.7<br>eAG(mmol/L) = 1.59 × A1C − 2.59<br>(Data in parentheses are 95% [[confidence interval]]s>)

{| class="wikitable" style="text-align:center; margin:auto;"
|-
! colspan="2" |HbA<sub>1c</sub> || colspan="2" |{{abbr|eAG|estimated average glucose}}
|-
! % || mmol/mol<ref>{{cite web |title=Change to HbA1c values |publisher=[[Diabetes UK]] |date=2013 |url=http://www.diabetes.org.uk/Professionals/Publications-reports-and-resources/Tools/Changes-to-HbA1c-values/ |url-status=dead |archive-url=https://web.archive.org/web/20130726032802/http://www.diabetes.org.uk/Professionals/Publications-reports-and-resources/Tools/Changes-to-HbA1c-values/ |archive-date=2013-07-26}}</ref> || mmol/L || mg/dL
|-
| 5 || 31 || 5.4 (4.2–6.7) || 97 (76–120)
|-
| 6 || 42 || 7.0 (5.5–8.5) || 126 (100–152)
|-
| 7 || 53 || 8.6 (6.8–10.3) || 154 (123–185)
|-
| 8 || 64 || 10.2 (8.1–12.1) || 183 (147–217)
|-
| 9 || 75 || 11.8 (9.4–13.9) || 212 (170–249)
|-
| 10 || 86 || 13.4 (10.7–15.7) || 240 (193–282)
|-
| 11 || 97 || 14.9 (12.0–17.5) || 269 (217–314)
|-
| 12 || 108 || 16.5 (13.3–19.3) || 298 (240–347)
|-
| 13 || 119 || 18.1 (15–21) || 326 (260–380)
|-
| 14 || 130 || 19.7 (16–23) || 355 (290–410)
|-
| 15 || 140 || 21.3 (17–25) || 384 (310–440)
|-
| 16 || 151 || 22.9 (19–26) || 413 (330–480)
|-
| 17 || 162 || 24.5 (20–28) || 441 (460–510)
|-
| 18 || 173 || 26.1 (21–30) || 470 (380–540)
|-
| 19 || 184 || 27.7 (23–32) ||499 (410–570)
|}

===Normal, prediabetic, and diabetic ranges===
The 2010 [[American Diabetes Association]] Standards of Medical Care in Diabetes added the HbA<sub>1c</sub> ≥ 48&nbsp;mmol/mol (≥6.5 DCCT %) as another criterion for the diagnosis of diabetes.<ref name="care.diabetesjournals.org">{{cite journal |title=Executive summary: Standards of medical care in diabetes — 2010 |journal=Diabetes Care |volume=33 |issue=Suppl 1 |pages=S4–S10 |date=January 2010 |pmid=20042774 |doi=10.2337/dc10-S004 |pmc=2797389 |url=http://care.diabetesjournals.org/content/33/Supplement_1/S4.extract |access-date=2010-01-02 |url-status=live |archive-url=https://web.archive.org/web/20100113200756/http://care.diabetesjournals.org/content/33/Supplement_1/S4.extract |archive-date=2010-01-13}}</ref>
{| class="wikitable"
|+Diagnostic standard for HbA1c in diabetes<ref>{{cite web |title=Diagnosing Diabetes and Learning About Prediabetes |website=American Diabetes Association |url=http://www.diabetes.org/diabetes-basics/diagnosis/ |access-date=2 December 2018 |url-status=live |archive-url=https://web.archive.org/web/20170728020224/http://www.diabetes.org/diabetes-basics/diagnosis/ |archive-date=28 July 2017}}</ref>
!Diagnosis
! "IFCC" HbA<sub>1c</sub>
! "DCCT" HbA<sub>1c</sub>
! "Mono S" HbA<sub>1c</sub>
|-
| Normal
| < 40 mmol/mol
| < 5.7%
| < 4.7%
|-
| Prediabetes
| 40–47 mmol/mol
| 5.7–6.4%
| 4.7–5.4%
|-
| Diabetes
| ≥ 48 mmol/mol
| ≥ 6.5%
| > 5.5%
|}

==Indications and uses==
Glycated hemoglobin testing is recommended for both checking the blood sugar control in people who might be prediabetic and monitoring blood sugar control in patients with more elevated levels, termed diabetes mellitus. For a single blood sample, it provides far more revealing information on glycemic behavior than a fasting blood sugar value. However, fasting blood sugar tests are crucial in making treatment decisions. The American Diabetes Association guidelines are similar to others in advising that the glycated hemoglobin test be performed at least twice a year in patients with diabetes who are meeting treatment goals (and who have stable glycemic control) and quarterly in patients with diabetes whose therapy has changed or who are not meeting glycemic goals.<ref>{{cite journal |author=American Diabetes Association |title=Standards of medical care in diabetes |journal=Diabetes Care |volume=30 |issue=Suppl 1 |pages=S4–S41 |year=2007 |pmid=17192377 |doi=10.2337/dc07-S004 |doi-access=free}}</ref><ref name="2022 ADA Guidelines" />

Glycated hemoglobin measurement is not appropriate where a change in diet or treatment has been made within six weeks. Likewise, the test assumes a normal red blood cell aging process and mix of hemoglobin subtypes (predominantly HbA in normal adults). Hence, people with recent blood loss, [[hemolytic anemia]], or genetic differences in the hemoglobin molecule ([[hemoglobinopathy]]) such as [[sickle-cell disease]] and other conditions, as well as those who have donated blood recently, are not suitable for this test.<ref>{{cite journal |last=Klonoff |first=David C. |date=2019-03-22 |title=Hemoglobinopathies and Hemoglobin A1c in Diabetes Mellitus |journal=Journal of Diabetes Science and Technology |volume=14 |issue=1 |pages=3–7 |pmid=30897962 |doi=10.1177/1932296819841698 |pmc=7189151}}</ref>

Due to glycated hemoglobin's variability, additional measures should be checked in patients at or near recommended goals. People with HbA<sub>1c</sub> values at 64&nbsp;mmol/mol or less should be provided additional testing to determine whether the HbA<sub>1c</sub> values are due to averaging out high blood glucose ([[hyperglycemia]]) with low blood glucose ([[hypoglycemia]]) or the HbA<sub>1c</sub> is more reflective of an elevated blood glucose that does not vary much throughout the day. Devices such as continuous [[blood glucose monitoring]] allow people with diabetes to determine their blood glucose levels on a continuous basis, testing every few minutes. Continuous use of blood glucose monitors is becoming more common, and the devices are covered by many health insurance plans, including [[Medicare (United States)|Medicare]] in the United States. The supplies tend to be expensive, since the sensors must be changed at least every 2 weeks. Another useful test in determining if HbA<sub>1c</sub> values are due to wide variations of blood glucose throughout the day is [[1,5-Anhydroglucitol|1,5-anhydroglucitol]], also known as [[GlycoMark]]. GlycoMark reflects only the times that the person experiences hyperglycemia above 180&nbsp;mg/dL over a two-week period.{{citation needed|date=July 2020}}

Concentrations of hemoglobin A1 (HbA1) are increased, both in diabetic patients and in patients with [[kidney failure]], when measured by [[ion-exchange chromatography]]. The thiobarbituric acid method (a chemical method specific for the detection of glycation) shows that patients with kidney failure have values for glycated hemoglobin similar to those observed in normal subjects, suggesting that the high values in these patients are a result of binding of something other than glucose to hemoglobin.<ref>{{cite journal |vauthors=Bannon P, Lessard F, Lepage R, Joly JG, Dufresne L |title=Glycated hemoglobin in uremic patients as measured by affinity and ion-exchange chromatography |journal=Clin Chem |volume=30 |issue=3 |pages=485–6 |date=March 1984 |pmid=6697506 |doi=10.1093/clinchem/30.3.485 }}</ref>

In [[autoimmune hemolytic anemia]], concentrations of HbA1 is undetectable. Administration of [[prednisolone]] will allow the HbA1 to be detected.<ref>{{cite web |title=Undetectable Glycosylated Hemoglobin in Autoimmune Hemolytic Anemia |website=repository.oai.yamaguchi-u.ac.jp |url=http://repository.oai.yamaguchi-u.ac.jp/yunoca/A02/A020052000103.pdf |access-date=2009-08-31 |url-status=live |archive-url=https://web.archive.org/web/20110716170454/http://repository.oai.yamaguchi-u.ac.jp/yunoca/A02/A020052000103.pdf |archive-date=2011-07-16}}</ref> The alternative [[fructosamine]] test may be used in these circumstances and it also reflects an average of blood glucose levels over the preceding 2 to 3 weeks.<ref>{{cite journal |vauthors=Freitas PA, Ehlert LR, Camargo JL |title=Glycated albumin: a potential biomarker in diabetes |journal=Arch Endocrinol Metab |volume=61 |issue=3 |pages=296–304 |date=2017 |pmid=28699985 |pmc=10118799 |doi=10.1590/2359-3997000000272 }}</ref>

All the major institutions such as the International Expert Committee Report, drawn from the International Diabetes Federation, the European Association for the Study of Diabetes, and the American Diabetes Association, suggest the HbA<sub>1c</sub> level of 48&nbsp;mmol/mol (6.5 DCCT %) as a diagnostic level.<ref>{{cite journal |author=The International Expert Committee |title=International expert committee report on the role of the A1C assay in the diagnosis of diabetes |journal=Diabetes Care |volume=32 |issue=7 |pages=1327–34 |year=2009 |pmid=19502545 |doi=10.2337/dc09-9033 |pmc=2699715}}</ref> The Committee Report further states that, when HbA<sub>1c</sub> testing cannot be done, the fasting and glucose-tolerance tests be done. Screening for diabetes during pregnancy continues to require fasting and glucose-tolerance measurements for [[gestational diabetes]] at 24 to 28 weeks gestation, although glycated hemoglobin may be used for screening at the first prenatal visit.<ref name = "Sacks">{{cite journal |vauthors=Sacks DB, Arnold M, Bakris GL, Bruns DE, Horvath AR, Lernmark Å, Metzger BE, Nathan DM, Sue Kirkman M |title=Executive Summary: Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus |journal=Clin Chem |volume=69 |issue=8 |pages=777–784 |date=August 2023 |pmid=37562009 |doi=10.1093/clinchem/hvad079 |doi-access=free }}</ref>

==Modification by diet==
[[Meta-analysis]] has shown [[probiotic]]s to cause a statistically significant reduction in glycated hemoglobin in [[diabetes mellitus type 2|type-2 diabetics]].<ref name="pmid26899960">{{cite journal |vauthors=Sun J, Buys NJ |title=Glucose- and glycaemic factor-lowering effects of probiotics on diabetes: a meta-analysis of randomised placebo-controlled trials |journal=[[British Journal of Nutrition]] |volume=115 |issue=7 |pages=1167–77 |year=2016 |pmid=26899960 |doi=10.1017/S0007114516000076 |doi-access=free}}</ref> Trials with multiple strains of probiotics had statistically significant reductions in glycated hemoglobin, whereas trials with single strains did not.<ref name="pmid26899960"/>

==Standardization and traceability==
Most clinical studies recommend the use of HbA1c assays that are traceable to the DCCT assay.<ref>{{cite journal |vauthors=((Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C)) |title=The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus |journal=N Engl J Med |volume=329 |issue=14 |pages=977–986 |date=September 1993 |pmid=8366922 |doi=10.1056/NEJM199309303291401 }}</ref> The National Glycohemoglobin Standardization Program (NGSP) and IFCC have improved assay standardization.<ref name="Sacks" /> For initial diagnosis of diabetes, only HbA1c methods that are NGSP-certified should be used, not [[point-of-care testing]] devices.<ref name = "2022 ADA Guidelines">{{cite journal |author=((American Diabetes Association Professional Practice Committee)) |title=6. Glycemic Targets: Standards of Medical Care in Diabetes-2022 |journal=Diabetes Care |volume=45 |issue=Suppl 1 |pages=S83–S96 |date=January 2022 |pmid=34964868 |doi=10.2337/dc22-S006 }}</ref> Analytical performance has been a problem with earlier [[point-of-care]] devices for HbA1c testing, specifically large standard deviations and negative bias.<ref name="Sacks" />

==Veterinary medicine==
HbA1c testing has not been found useful in the monitoring during the treatment of cats and dogs with diabetes, and is not generally used; monitoring of [[fructosamine]] levels is favoured instead.<ref name="pmid17422317">{{cite journal |vauthors=Delack JB, Stogdale L |title=Glycosylated hemoglobin measurement in dogs and cats: implications for its utility in diabetic monitoring |journal=Can Vet J |volume=24 |issue=10 |pages=308–311 |date=October 1983 |pmid=17422317 |pmc=1790442}}</ref>

==See also==
* [[Diabetes mellitus]]
* [[Hemoglobin A2]]
* [[Prediabetes]]
* [[Proteopedia]]: [https://proteopedia.org/wiki/index.php/Glycated_hemoglobin Structure of glycated hemoglobin]

== Notes ==
{{Notefoot}}

==References==
{{Reflist}}

==External links==
{{Commons category}}
{{Scholia}}
* [https://www.niddk.nih.gov/health-information/diabetes Health Information: Diabetes] — National Institutes of Health (NIH): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
** [https://web.archive.org/web/20100221034416/http://diabetes.niddk.nih.gov/ National Diabetes Information Clearinghouse] — NIDDK (old site, archived 2010-02-21)
* [https://professional.diabetes.org/standards-of-care Standards of Care in Diabetes], American Diabetes Association Professional Practice Committee
** [https://ada.silverchair-cdn.com/ada/content_public/journal/care/issue/47/supplement_1/15/standards-of-care-2024.pdf Standards of Care in Diabetes — 2024] (pdf), American Diabetes Association Professional Practice Committee

{{Blood tests}}
{{Globins}}
{{Diabetes}}

[[Category:Blood tests]]
[[Category:Diabetes-related tests]]
[[Category:Diabetes]]
[[Category:Glucose]]
[[Category:Hemoglobins]]