The use of HbA_1c for new diagnosis of diabetes in those with hyperglycaemia on admission to or attendance at hospital urgently requires research

SUSAN E MANLEY,^1,2,3 ANDREAS KARWATH,^1,4,5,6 JOHN A WILLIAMS,^1,5,6,7 JONATHAN WEBBER,^1,8 RAJEEV P RAGHAVAN,⁹ BALDEV M SINGH,^9,10 CRAIG WEBSTER,¹¹ RACHEL A ROUND,^1,11 IRENE M STRATTON,^1,12,13 GEORGIOS V GKOUTOS,^{1,4,5,6,14,15,16*} GRAHAM A ROBERTS,^1,17,18,19* SAMIUL MOSTAFA,^1,2,8* SANDIP GHOSH,^1,20* ON BEHALF OF THE DIABETES TRANSLATIONAL RESEARCH GROUP (DTRG), QUEEN ELIZABETH HOSPITAL BIRMINGHAM AND BIRMINGHAM UNIVERSITY, *JOINT LAST AUTHORS

¹ Diabetes Translational Research Group, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
² College of Medical and Dental Sciences, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
³ Green Templeton College, University of Oxford, Oxford, UK
⁴ MRC Health Data Research UK (HDR UK) Midlands, Birmingham UK
⁵ College of Medical and Dental Sciences, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
⁶ Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
⁷ Mammalian Genetics Unit, Medical Research Council Harwell Institute, Harwell, UK
⁸ Diabetes Centre, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
⁹ Diabetes Endocrine Services, Diabetes Endocrine Centre, Location C28, New Cross Hospital, Royal Wolverhampton Trust, Wolverhampton, UK
¹⁰ Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK
¹¹ Clinical Laboratory Services, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
¹² University of Oxford, Oxford, UK
¹³ University of Southampton, Southampton, UK
¹⁴ NIHR Experimental Cancer Medicine Centre, Birmingham, UK
¹⁵ NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham, UK
¹⁶ NIHR Biomedical Research Centre, Birmingham, UK
¹⁷ Diabetes Research Unit (Cymru), Grove Building, Swansea University, Swansea, UK
¹⁸ HRB-Clinical Research Facility – Cork University College, Cork, Ireland
¹⁹ Department of Endocrinology and Diabetes, University Hospital Waterford, Waterford, Ireland
²⁰ Department of Endocrinology, Zulekha Hospital Sharjah, UAE

Address for correspondence: Dr Susan Manley
26 Hayward Road, Oxford, OX2 8LW, UK
E-mail: se.manley@btinternet.com

https://doi.org/10.15277/bjd.2022.386

Abstract

The prevalence of diabetes in Birmingham is 11% but it is 22% in hospital inpatients. Queen Elizabeth Hospital in Birmingham (QEHB) serves a multi-ethnic population with 6% Afro-Caribbean, 19% South Asian and 70% White European.

A clinical audit of 18,965 emergency admissions to QEHB showed that 5% were undiagnosed but had admission glucose in the ‘diabetes’ range and 16% were in the ‘at risk’ range. The proportion of Afro-Caribbeans (7%) and South Asians (8%) in the ‘diabetes’ range was higher than White Europeans (5%). Given the magnitude of the problem, this paper explores the issues concerning the use of reflex HbA_1c testing in the UK for diagnosis of diabetes in hospital admissions. HbA_1c testing is suitable for most patients but conditions affecting red blood cell turnover invalidate the results in a small number of people.

However, there are pertinent questions relating to the introduction of such testing in the NHS on a routine basis. Literature searches on a topical question ‘Is hyperglycaemia identified during emergency admission/attendance acted upon?’, were performed from 2016 to 2021 and 2016 to 2022. They identified 21 different, relevant, research papers - 5 from Australia, 9 from Europe including 4 from the UK, 5 from America and 1 each from Canada and Africa. These papers revealed an absence of established procedures for the management and follow-up of routinely detected hyperglycaemia using HbA_1c when no previous diabetes diagnosis was recorded.

Further work is required to determine the role of reflex HbA_1c testing for diagnosis of diabetes in admissions with hyperglycaemia, and the cost-effectiveness and role of point-of-care HbA_1c testing.

Br J Diabetes 2022;22:95-104

Key words: HbA_1c, inpatients, diagnosis of diabetes

Introduction

The in-hospital prevalence of known diabetes in Birmingham is 22%, with the local population prevalence 11%.¹ Over and above this, acute illnesses can cause stress- induced hyperglycaemia, which is associated with increased mortality in medical and surgical patients.² Although stress induced hyperglycaemia does usually resolve, up to 60% of patients with stress hyperglycaemia may have a diagnosis of diabetes based on stepwise testing as per American Diabetes Association (ADA) criteria.³

Inpatient mortality is nine times greater in the short term for patients with newly diagnosed hyperglycaemia than normoglycaemia, and five times more than for diabetes. Mortality for those with de novo hyperglycaemia is 16% compared to 3% if diabetes is already diagnosed and 2% in those with normo- glycaemia.⁴

An audit was undertaken locally in Queen Elizabeth Hospital Birmingham (QEHB), a large university hospital and major trauma centre in the West Midlands serving a multi-ethnic population. It recorded >30,000 admission plasma glucose results with glucose measured on capillary blood using point-of-care glucose meters (75%), blood gas machines on arterial/venous whole blood (18%) and in the laboratory on blood collected into fluoride oxalate vacutainers (7%) with all the glucose results reported as plasma. High blood glucose on admission to hospital in those without diabetes was common. Routine random blood glucose measurement on admission identified glucose in the ‘diabetes’ range (>11.0 mmol/L) in 5% of 18,965 emergency hospital admissions between 2014 and 2015,⁵ and 16% in the ‘at risk’ range (7.8 to 11.0 mmol/L) in those without a prior diabetes diagnosis. More South Asians and Afro-Caribbeans were in the ‘diabetes’ range at 8% compared with 5% for White Europeans. The South Asian and Afro-Caribbean admissions were younger than White Europeans.

Ensuring that undiagnosed diabetes is identified in patients admitted to hospital is important, especially as hyperglycaemia observed in emergency admissions to hospital in those not previously diagnosed with diabetes may not be subject to further investigation,⁶ or followed up, as indicated in a recent literature review.⁷

The UK National Service Framework for Diabetes: Standards 2001 aims ‘to ensure that people with diabetes are identified as early as possible’ and states that ‘the NHS will develop, implement, and monitor strategies to identify people who do not know they have diabetes’.⁸

A report on the prospective measurement of HbA_1c in the acute setting published in 2016 provided evidence on the use of HbA_1c testing in hospital to identify those with undiagnosed diabetes.⁹

The ADA (2021) and Joint British Diabetes Societies (JBDS) (2020) have suggested HbA_1c testing to confirm diabetes in hospital admissions when random plasma glucose ≥7.8 mmol/L.^10,11 However, in-hospital studies^5,7,12 illustrate the complexity of decision making when the diagnosis of diabetes is based on a surrogate glycaemic marker and such testing is still not employed universally^7,12 nor adopted systematically in the UK.

Literature searches were performed in January 2021 and October 2022. Their aim was to locate papers on established procedures to identify people with no known history of diabetes who attended or were admitted to hospital via the emergency department and were found to have hyperglycaemia, and on their follow-up in the community.

Methods

Scoping literature searches of papers published from 2016 up to January 2021 and 24th October 2022 were performed. They were set up to identify articles if the keywords or phrases appeared in either the title or abstract. The Healthcare Databases Advanced Search (HDAS) interface was used for the first search and the second was performed using the OVID interface as the HDAS resource was no longer available. PubMed, MEDLINE and Embase databases, Table 1, were used to answer the question – ‘Is hyperglycaemia identified during emergency admission/attendance acted upon?’. Date limits were set for the MEDLINE and Embase searches, with those listed by PubMed as published prior to 2016 excluded. The research assistant screened the resulting papers for eligibility from the title and abstract. The search terms used are outlined in Table 1; they did not distinguish between attendance at the emergency department alone versus admission to hospital. The numbers of papers identified in the searches are outlined in Figure 1, prepared according to PRISMA 2009 guidance.^13,14

Results of literature searches
PubMed identified 328 papers, MEDLINE 105, 55 and 23 papers, and Embase 59 papers overall for the searches (Table 1 and Figure 1). From these 570 papers, 21 relevant records were followed up after duplicate papers, conference abstracts and letters were excluded.^5-7,9,15-30 Full text was available for 18 papers with abstracts for three entries. The relevant, research papers were from Europe (9, including 4 from the UK), Australia (5), America (5), Canada (1) and East Africa (1). The paper referred to in the introduction published by this translational research group in 2016 was listed in the second search,⁹ as was the systematic review from the UK published in December 2021 by Thornton-Swan et al.⁷ Of the twelve relevant papers identified in their systematic review performed using PubMed and Embase, seven papers were published before 2016 when the searches reported here were started. Of the remaining five papers in the systematic review, three were identified in these searches (Table 2).

Ten papers reported on studies with fewer than 1,000 participants, four between 1,000 and 6,000 participants, four between 10,000 and 20,000 participants and two with more  than 50,000 participants with the other being the systematic review. The length of the studies and size of the institutions also varied. The weaknesses of the various studies included retrospective design, location at only one hospital site, systematic bias in the population screened, limitations of random blood glucose testing, availability of HbA_1c testing, inability to evaluate the accuracy of diagnosis using HbA_1c, and coding inaccuracies.

All the papers noted that hyperglycaemia was common in people in emergency departments, but none reported on well established procedures to confirm a diabetes diagnosis or protocols for follow-up. It might be expected that admissions with hyperglycaemia would be more likely to receive an appropriate diabetes diagnosis but there was no consistency in this aspect of patient care. In one paper, it was noted that ‘clinically important HbA_1c results were rarely communicated to GPs’.⁶

Discussion

At present WHO have only adopted the recommendation to use HbA_1c ≥48 mmol/mol (6.5%) for diagnosis of T2DM in the com- munity.³¹ For this reason, requests from GPs for an oral glucose tolerance test (OGTT), which are more expensive, are now rare in the UK and only performed for patients in whom HbA_1c testing would be inappropriate. More recently, the Diabetes Remission Clinical Trial (DiRECT) has recommended use of HbA_1c to define remission of T2DM at least three months after cessation of glucose-lowering pharmacotherapy,³² with delivery of the study protocol possible now in primary care with appropriate support and training.³³ Thus, whilst HbA_1c is now widely used for diagnosis in the UK primary care setting, it is not used consistently in hospital inpatients.

Stress hyperglycaemia may reverse without intervention when the underlying medical cause is resolved. In contrast, hyperglycaemia associated with undiagnosed diabetes is likely to have been present for long enough to affect HbA_1c.⁹

Theoretically, HbA_1c can thus be used to distinguish between stress hyperglycaemia and chronic disease. Jones et al in 2016 conclude that ‘the implementation of a hospital protocol whereby hyperglycaemia is recognized and automatically triggers a reflex HbA_1c test should become part of normal routines.’³⁰

There is a paucity of evidence on how many hospital admissions with glucose in the ‘diabetes’ range would benefit from additional HbA_1c testing to diagnose diabetes. Previous studies have illustrated the issues associated with other measures of glycaemia, such as fasting glucose or OGTT, with the constraints involved in terms of preparation of patients and the time and staffing involved.⁷ They highlight the need for appropriate additional testing, the influence of stress hyperglycaemia and the challenges of appropriate follow-up.^6,12

As the literature searches reveal, HbA_1c is used more in American and Australian hospitals for diagnosis but there are major issues with consistency in the definition of hyperglycaemia in clinical practice.⁷ Screening for diabetes and pre-diabetes using HbA_1c in admissions is recommended when glucose is ≥7.8 mmol/L by ADA standards for medical care,¹⁰ and in JBDS guidance.¹¹

The published systematic review⁷ concurred with the searches presented here, concluding that more research is required to identify the optimal glucose value for addition of HbA_1c to diagnose diabetes in hospital admissions and that standardised protocols are required for routine practice.

There is potential for medico-legal liability if a diagnosis is not made or is made without robust follow-up.⁶ As far as measurement is concerned, although the correlation between point-of-care test- ing (POCT) and laboratory HbA_1c testing is high,³⁴ the ADA does not recommend using POCT devices for diagnosis of diabetes at sites where the required education, training and oversight of performance are not in place.³⁵

It is also important to be mindful of drug regimens, ethnicity and comorbidities when requesting HbA_1c in hospitalised patients who are more likely to present with multiple comorbidities.

Any medical condition or drug that alters erythrocyte lifespan can potentially affect HbA_1c. If the proportion of younger red blood cells is increased, with less exposure of haemoglobin to glucose than normal, HbA_1c values are depressed;³⁶ and similarly (although less often observed) increased if red cell life span is lengthened e.g. in alpha-1-antitrypsin disorder,³⁶ and some thalassaemias and anaemias.^37,38

Ethnicity can also influence how HbA_1c relates to glucose. In Birmingham, HbA_1c levels were 10% higher relative to admission glucose levels in South Asians and Afro-Caribbeans than White Europeans.³⁹ This may reflect haematological differences affecting red blood cell lifespan. Questions have been raised as to whether HbA_1c cut-offs for diagnostic purposes should be determined by ethnicity.⁴⁰

A few hospitals already cancel HbA_1c requests electronically when abnormal haemoglobin is present. It should be possible to flag on the patient’s record when HbA_1c may not be accurate if conditions such as ethnicity,⁴¹ use of certain drugs such as dapsone and ribavirin, and other illnesses that affect red blood cell turnover are present.⁴²

The team of authors (clinicians, clinical and laboratory scientists, statisticians and data visualists) have compiled a list of important questions to be addressed about additional HbA_1c testing for diagnostic purposes in a hospital setting (Table 3) and a possible flowchart (Figure 2) based on their experience and expertise.

A possible approach using flexi-testing

A digital approach, involving flexi-testing appropriate inpatients with HbA_1c to diagnose diabetes and preliminary algorithms for use in primary and secondary care to detect any inaccuracy, would permit practice of translational and precision medicine (Figure 2). HbA_1c can be added automatically when an EDTA sample is avail- able from a full blood count request or an EDTA sample requested for the test.

Flexi-testing requires liaison between the hospital laboratory and electronic patient record system to identify people with ad- mission glucose in the ‘diabetes’ range who have not previously been diagnosed with diabetes. If this electronic facility is not available, the test can be requested by clinical staff when hyper- glycaemia is flagged on the electronic patient record.

Consideration of additional HbA_1c testing for those in the ‘at risk’ range will depend on the prevalence and cost, and negotiation with relevant national clinical bodies. In terms of costing, the consumables for HbA_1c, a routine test, are higher than for glucose but the actual cost to the NHS involves the percentage of admissions requiring the test, whether they would be eligible in other diabetes protocols and the actual costing process in hospital for the laboratory and clinical staff input.

It may be possible to consider omitting patients who would be routinely tested elsewhere currently from the calculations on costing e.g. those over 40 years-old who are eligible for HbA_1c testing by their GP and those with symptoms or complications of diabetes on admission to hospital. There may be differences to the workload generated in hospitals across the UK as the prevalence of glucose in the ‘diabetes’ range on admission to hospital is higher in South Asians and Afro-Caribbeans.⁵ None of this has been established accurately yet due to lack of prospective data.

In conclusion

The overall message is of a missed opportunity for diabetes diagnosis in hospitals given the high population prevalence,¹ the burden of diabetes related to hospital admissions and consequences resulting from a delayed diagnosis.⁴³ There is potential for identifying diabetes by additional testing with HbA_1c during an acute hospital admission for those with hyperglycaemia but no previous diabetes diagnosis.

Although currently ADA and JBDS advise the addition of HbA_1c when glucose ≥7.8 mmol/L, perhaps a more nuanced approach should be offered now as this cut-off is not being followed up systematically in UK hospitals or elsewhere for various reasons. However, there are caveats to widespread HbA_1c testing in the UK, and clarity is needed around the exact approach to be adopted.

In future, a digital approach to confirming a diagnosis of diabetes in hospital patients is required with evidence-based standard algorithms and protocols which include flexi-testing with HbA_1c derived by research methodology. The overall cost/benefit of this should be obtained from such studies. An expert task force could design a UK-wide, prospective study to arrive at an evidence-based approach to a program for such a digital pathway.

Conflict of interest SEM and RAR received funding from University Hospital Birmingham Charities and from the GA Roberts Research Fund. RPR has received consultation and/or lecture fees or unrestricted travel grants from Novo Nordisk, Eli Lilly, Boehringer Ingelheim (BI), AstraZeneca (AZ), Takeda, NAPP, Abbott Diabetes. SG has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; speaker honorarium for AZ, BI and Novo Nordisk; support for attending meetings and/or travel; supported with educational grant to attend meeting for BI, Novo Nordisk, Eli Lilly. All others authors have no conflicts of interest to declare in relation to this paper.

Funding The DTRG acknowledges support from the GA Roberts Research Fund and University Hospitals Birmingham Charity. AK acknowledges support from the UK Medical research Council (MRC grant MR/S003991/1; JAW acknowledges support from the National Human Genome Research Institute of the National Institutes of Health under Award Number UM1HG006370; GVG acknowledges support from National Institute for Health Research (NIHR) Birmingham Experimental Cancer Medicine Centre, NIHR Birmingham Surgical Reconstruction and Microbiology Research Centre, NanoCommons H2020-EU (731032), NIHR Birmingham Biomedical Research Centre and the MRC Heath Data Research UK (HDRUK/CFC/01), an initiative funded by UK Research and Innovation, Department of Health and Social Care (England) and the devolved administrations, and leading medical research charities. The funding organisations had no role in the design of this study, data collection, analysis or interpretation, or preparation of the manuscript, and did not approve or disapprove of, or delay publication of the work.

Acknowledgements Dr Susan Manley is a member of the US National Glycohemoglobin Standardization Program Advisory Committee, Joint British Diabetes Societies Inpatient Committee and National Advisory Panel for Care Home Diabetes. Irene Stratton is a member of the Diabetes UK Acute Care Study Group. The authors are grateful for support and encouragement from Janet Smith, previously head of Clinical Biochemistry, University Hospitals Birmingham NHS Foundation Trust and the laboratory for the Birmingham UKPDS centre.

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