Managing and diagnosing diabetes at the point-of-care

Clinical decisions need to be made at the earliest possible time to facilitate the administration of quick and accurate treatment plans. Point of care testing (POCT) enables tests to be convenient and fast, making them suitable for use with a broad range of patients, including diabetics. Glycated hemoglobin (HbA1c) is commonly tested in diabetics as it provides a reliable measure of glycemic control (Figure 1). However, the role of HbA1c in the diagnosis of diabetes has only more recently been documented. HbA1c levels reflect average circulating glucose levels over the lifespan of red blood cells (2-3 months). Once hemoglobin molecules have been glycated, they become highly stable, enabling a greater level of clinical information to be obtained from them than a single glucose measurement taken at a particular point in time.

by Gavin Jones, Diabetes Product Manager, EKF Diagnostics

By taking serial HbA1c measurements, an individual’s control over their glucose levels can be assessed in response to changes in management strategies. Measurements should be taken every 2-6 months with target HbA1c levels set individually and therapy adjusted accordingly to provide the most effective treatment (1). The target ranges of HbA1c for diabetic patients, depending on their risk of severe hypoglycemia, cardiovascular status and co-morbidities, should be set between 6.5 – 7.5% DCCT (48 – 58 mmol/mol), with the non-diabetic reference range being 4.0 – 6.0% DCCT (20 – 42 mmol/mol). One point for consideration is that HbA1c results may be affected by any condition that leads to a change in red blood cell survival. But even then, HbA1c can be used to detect trends in a patient’s glycemic control.

HbA1c in POCT-based diabetes monitoring
HbA1c determination was originally based on methods such as ion exchange and affinity chromatography with alternative affinity and immunological methods following later, taking HbA1c into the POC environment.

Typically, when using laboratory-based testing, patients with existing diabetes are monitored for HbA1c every 2-6 months, requiring a visit to a nurse or phlebotomist and a follow-up appointment 1 to 2 weeks later to discuss the results. Use of POCT would mean that after just one visit, patients can leave with their results, eliminating the need for a follow-up appointment. By enabling an earlier therapeutic decision, diabetes control can be improved whilst also providing economic benefits in terms of cost and time.

Diabetes diagnosis
The benefits of HbA1c in the management of diabetes can also be directly applied to the diagnosis of diabetes. Unlike glucose levels, which are affected by what has been eaten and drunk in the previous 2-3 hours, the measurement of HbA1c levels does not require fasting. As a simple and immediate test for diabetes, POC HbA1c can support the early identification of at-risk individuals. This would rapidly enable them to make small changes to their lifestyle to significantly reduce the risk of developing type 2 diabetes.

Patients diagnosed with diabetes who are able to maintain low blood HbA1c levels also have a significantly reduced chance of complications after diagnosis (2); early detection by POCT can reduce this risk even further. The ability to rapidly assess and change these risk outcomes has significant health benefits and reduces the costs associated with recurrent leg ulcers, blindness, heart disease and stroke, for example, all of which are conditions and complications commonly associated with type 2 diabetes.

The World Health Organization (WHO) has recommended the use of HbA1c for the diagnosis of diabetes (3). In the UK for example, the National Institute for Clinical Excellence (NICE) has published guidelines for diabetes prevention which aim to identify people at high risk of type 2 diabetes and offer cost-effective, appropriate interventions to prevent or delay onset (4). Used in conjunction with a lifestyle health risk assessment, these guidelines advocate the monitoring of HbA1c levels to allow healthcare providers to  advise individuals on treatment regimens, depending on their classification as low, moderate or high risk. Current guidance, therefore, supports the use of HbA1c in screening for type 2 diabetes, and in the management of patients with diabetes. The use of POCT could improve the management of patients with established diabetes in both primary and secondary care settings and enable earlier type 2 diabetes diagnosis.

What to look for in a POC HbA1c analyser
Most POC HbA1c analysers use a single drop of blood (4-10 µL), which is applied to a reagent cartridge. The cartridge is then directly inserted into a desktop device for analysis. Time to results is generally between 3 to 10 minutes, depending on the analyzer. This quick turn-around time, in combination with simple operation, is key to maintaining effective POC testing.

Simplicity
To minimize human error and the subsequent need for repeat testing, a POC analyser should be as easy as possible to use. Also the analyser should be highly intuitive, requiring little user training. Features that support ease-of-use include ready-to-use reagent cartridges which can be inserted straight into the analyser. The blood sample can then be added directly, without the need for premixing or pipetting. Minimizing the number of steps in the procedure not only reduces the potential for user error, but also helps to standardize results by eliminating variation from different users.

Audit trails
For patient safety purposes, audit trails must be readily available. Use of barcode scanning for patient and user identification, as well as confirmation of the batch of reagents and controls used, ensures an analyser can provide such information in a timely manner. Two levels of quality controls that are recorded and held within the analyser’s memory are also ideal for auditing purposes.

Certification
Certification of the analyser in order to confirm delivery of accurate, standardized results should also be a key consideration. In an effort to standardize HbA1c results, the AACC set up the ’National Glycohemoglobin Standardization Program’ (NGSP) in 1996. In parallel, the International Federation of Clinical Chemistry (IFCC) developed reference methods for glycated hemoglobin. In 2006 and 2007, an international consensus between IFCC and AACC was agreed upon (5).

The calibration and certification of laboratories and manufacturers to the same standards has improved the conformity of results. However, in practice, differences can still be observed among technologies and between individual systems. These observed differences arise because of heterogeneity of hemoglobins, underlying differences in technologies (e.g. ion exchange, boronate affinity, immunoassay), calibration drifts or lot to lot variability. Providing the manufacturer follows the recommendations of the IFCC and NGSP to ensure instruments and reagents are accurately aligned and traceable to the reference method, this should not be a problem.

Methodology
There are POC HbA1c analysers available (e.g., the Quo-Lab, EKF Diagnostics, Cardiff, UK) (Figure 2) where results are not affected by hemoglobin variants (which do not result in reduced erythrocyte life span), labile glycated hemoglobin or hematocrit levels. Such analysers use Boronate Fluorescence Quenching Technology (BFQT) (6) (Figure 3) which is associated with simple, yet powerful multiple optical measurements. This is based on well-documented boronate affinity chromatography systems used in reference laboratories. However, as BFQT does not require chromatographic separation, the methodology allows for fast, simple and accurate POC measurement of HbA1c to deliver comparable results to chromatography-based techniques.

Summary
Type 2 diabetes can be managed easily and effectively through the monitoring of HbA1c levels, as opposed to blood glucose. POC diagnosis enables early detection in higher risk patients, before any additional complications arise. POCT therefore not only improves patient access to testing, but provides accurate diagnoses there and then. Treatment strategies can be determined immediately, eliminating the need for a follow-up visit to discuss the results. The ability for diagnosis to occur near to the patient provides greater convenience, thus increasing the likelihood of compliance.

When selecting an analyser for use at the POC, users need to bear in mind that it needs to be a convenient and appropriate option. The focus should be on meeting regulatory requirements, as well as ease of use in order to ensure rapid testing, with accurate, standardized resulting data.

References:
1. Diabetes UK. HbA1c Standardization: Information for Clinical Healthcare Professionals. 2009. http://www.diabetes.org.uk/Guide-to-diabetes/Monitoring/Blood_glucose/Glycated_haemoglobin_HbA1c_and_fructosamine/HbA1c_Standardisation_Information_for_Clinical_Healthcare_Professional.
2. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86.
3. World Health Organization. Use of glycated hemoglobin (HbA1c) in the diagnosis of diabetes mellitus. 2011. www.who.int/diabetes/publications/report-hba1c_2011.pdf.
4. National Institute for Health and Clinical Excellence. Preventing type 2 diabetes: risk identification and interventions for individuals at high risk. 2012. www.nice.org.uk/nicemedia/live/13791/59951/59951.pdf.
5. Geistanger A, Arends S, Berding C, Hoshino T, Jeppsson JO, Little R, Siebelder C, Weykamp C; on behalf of the IFCC Working Group on Standardization of Hemoglobin A1c. 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. Clin Chem. 2008 Aug;54(8):1379-85.
6. Wilson DH, Bogacz JP, Forsythe CM, Turk PJ, Lane TL, Gates RC and Brandt DR. Fully automated assay of glycohemoglobin with the Abbott IMx analyzer: novel approaches for separation and detection. Clinical Chemistry October 1993 vol. 39 no. 10 2090-2097