What is the next diabetes investigation?

Learning points

• Haemoglobin A_1c (HbA_1c) can now be used as an alternative test to glucose concentration for diagnosing type 2 diabetes or identifying people at high risk of developing the disease
• Be aware of the conditions in which use of HbA_1c would be inappropriate, including suspected type 1 diabetes, pregnancy, acute medical illness, and kidney failure
• Also be mindful of conditions that might affect HbA_1c, such as abnormal haemoglobins and anaemia
• Do not routinely test both glucose and HbA_1c in the same patient

A 48 year old man presented to his general practitioner with a 12 month history of fatigue (which he put down to long office hours) and with urinary frequency. He had no previous health problems, his blood pressure was 145/85 mm Hg, and his body mass index was 29. His father had developed type 2 diabetes at the age of 65 years, and his paternal grandmother had been found to have diabetes at the age of about 60 following the development of a gangrenous toe. The patient’s dipstick urine test showed no glycosuria, ketonuria, proteinuria, blood, leucocytes, or nitrites.

All the possible causes of fatigue should be considered,1 but given the patient’s symptoms and his risk factors for developing type 2 diabetes, including family history and being overweight, a diagnosis of diabetes certainly needs to be excluded. Tests for diabetes are used to evaluate both patients with symptoms (as in this case) and asymptomatic patients who have been identified by a validated risk assessment tool as being at high risk of developing type 2 diabetes.2

Using glucose to diagnose diabetes

Since the early 20th century, the diagnosis of diabetes has been based on the measurement of glucose concentrations in the blood. This usually takes the form of laboratory measured fasting plasma glucose concentration and, when indicated, a glucose concentration two hours after an oral glucose load. However, “random” (post-prandial) measurement can suffice if it is unequivocally raised, especially in a patient with symptoms. The diagnostic threshold concentrations for glucose in use by the World Health Organization are defined as those above which it is known that a person will be at high risk of developing, if they are not already present, the microvascular complications of diabetes, particularly retinopathy.3 In non-pregnant adults, the main indication for an oral glucose tolerance test is when the fasting plasma glucose concentration lies between the values suggestive of normality and overt diabetes—namely, in the impaired fasting glucose range of 6.1-6.9 mmol/L inclusive. The two hour post-glucose load measurement can then help to distinguish patients who have solely impaired fasting glucose from those who have both impaired fasting glucose and impaired glucose tolerance (plasma glucose concentration 7.8 to <11.1 mmol/L) and from those who can be diagnosed as having diabetes purely on the basis of their two hour glucose result being 11.1 mmol/L or above (box 1).

Box 1 Venous plasma glucose thresholds3

Diabetes mellitus

• Fasting glucose ≥7.0 mmol/L or
• Two hour post-glucose load ≥11.1 mmol/L or
• Random glucose ≥11.1 mmol/L

Impaired glucose tolerance

• Fasting (if measured) <7.0 mmol/L and
• Two hour post-glucose load ≥7.8 to <11.1 mmol/L

Impaired fasting glucose

• Fasting glucose ≥6.1 to <7.0 mmol/L and
• (If measured) two hour post-glucose load <7.8 mmol/L

• For asymptomatic patients, at least one additional glucose test result with a value in diabetic range is essential for diagnosis. Impaired glucose regulation refers to a patient who has either impaired fasting glucose or impaired glucose tolerance

Using haemoglobin A_1c to diagnose type 2 diabetes

As can be seen, measuring glucose in the blood to diagnose diabetes can be inconvenient for patients, as they are usually required to fast overnight; if an oral glucose tolerance test is needed, the procedure is laborious, time consuming, and costly. For this reason, in recent years, more consideration has been given to whether measurement of glycated haemoglobin—haemoglobin A_1c (HbA_1c)—might be a valid alternative to glucose as a diagnostic test for diabetes, although this concept has led to controversy.4 Quite apart from not requiring a patient to fast overnight, HbA_1c measurement has several other potential advantages over glucose (box 2), including its property of giving an indication of glycaemia over several preceding weeks rather than at a single time point and, partly as a consequence, reduced day to day variation within an individual compared with glucose.5

Box 2 Advantages of HbA_1c over glucose in diagnosing type 2 diabetes

• Does not require patients to fast, take a glucose solution (which can sometimes cause nausea), or return for second blood test after two hours
• Assesses glycaemia over previous weeks or months
• Lower biological variability than fasting glucose or two hour post-glucose load concentration
• Fewer pre-analytical concerns, including time to analysis
• Already used to guide management of diabetes
• Standardisation of HbA_1c measurement should help with harmonising results between laboratories

Advances in the global standardisation of HbA_1c measurement culminated in WHO publishing advice in 2011 that recommends an HbA_1c threshold of 48 mmol/mol (6.5%) or above for the diagnosis of type 2 diabetes but does not give specific guidance below this single value.6 Since then, an expert committee in the United Kingdom, which included seven clinical professional bodies and National Health Service organisations, came to a consensus recommending that a diagnosis of diabetes should be made only after a confirmed raised HbA_1c value. The committee also introduced a new category of patients who are judged as being at high risk of developing diabetes solely on the basis of an HbA_1c value of 42-47 mmol/mol (6.0-6.4%) (figure⇓).7

Using haemoglobin A_1c (HbA_1c) to diagnose type 2 diabetes in non-urgent situations. *HbA_1c values >120 mmol/mol (13.1%) are likely to indicate marked hyperglycaemia that may need urgent assessment

When not to use HbA_1c to diagnose diabetes

One of the main advantages of HbA_1c—that it can give an indication of previous glycaemia—is also a disadvantage when hyperglycaemia could have developed rapidly, as rises in HbA_1c will lag behind those of glucose. This is why the test is unsuitable in clinical situations such as suspected type 1 diabetes, as well as many of the others described in box 3. Also, most laboratories are able to analyse glucose much more rapidly than HbA_1c, so requesting HbA_1c could introduce delay in an acute situation. In kidney failure (chronic kidney disease stage 5), the picture is complicated by patients often having a combination of haemolytic, iron deficiency, and chronic inflammation anaemias as well as forming urea derived carbamylated HbA_1c, which can also affect some HbA_1c analyses. Several treatments for HIV are also known to influence the HbA_1c value independently of glycaemia. Measurement of HbA_1c is not recommended when determining whether a pregnant woman has gestational diabetes, as it seems to be a poorer predictor of adverse fetal outcome than is glucose.8

Box 3 When not to use HbA_1c for diagnosis and when to be cautious

Do not use HbA_1c

• All children and young people
• Pregnancy—current or recent (<2 months)
• Suspected type 1 diabetes, at any age
• Short duration of symptoms of diabetes (<2 months)
• Patients at high risk of diabetes who are acutely ill
• Patients newly taking drug that may cause rapid rise in glucose, such as corticosteroids, antipsychotic drugs
• Acute pancreatic damage or pancreatic surgery
• Kidney failure
• Patients being treated for HIV infection

Be cautious in requesting or interpreting HbA_1c

• Patient has or may have abnormal haemoglobin
• Patient is anaemic (any cause)
• Patient is likely to have altered red cell lifespan (for example, post-splenectomy)
• Patient has had recent blood transfusion

Other cautions with using HbA_1c

Although HbA_1c should not be used in the situations already described, caution must also be exercised when using HbA_1c in the presence of an abnormal haemoglobin or in conditions that may affect red cell survival (box 3).7 For example, haemoglobin E will form HbE_1c instead of HbA_1c, which may lead to an incorrect assessment of HbA_1c depending on the particular measurement method used by the local laboratory. Haemolytic anaemia can cause low HbA_1c values compared with glucose measurements, and iron deficiency anaemia can cause a raised HbA_1c, although how much influence iron deficiency might have at the diagnostic threshold is not yet clear. After a splenectomy, the lifespan of red blood cells is often increased and so could lead to HbA_1c values that are higher than would be anticipated for the level of glycaemia.

HbA_1c increases with age beyond what can be explained by any changes in fasting glucose or two hour post-glucose load concentrations, and people with Afro-Caribbean or Asian heritage have higher HbA_1c values than do those from Europid descent, which also cannot be accounted for by differences in oral glucose tolerance test results. However, the relevance of these observations to the use of HbA_1c as a diagnostic test remains uncertain.7

Glucose or HbA_1c for diagnosis?

The diagnosis of type 2 diabetes can be made on the basis of either HbA_1c or blood glucose criteria being met. However, these will not identify an identical population of people, as they are not completely concordant with one another.4 For this reason, UK recommendations advise that only one or other test is used to follow the same patient and not a mixture of the two. So if HbA_1c shows a patient to be at high risk of diabetes, he or she should be followed up using the same test rather than blood glucose also being measured at the same time or later. The exception is if HbA_1c measurement is initially or subsequently identified as being inappropriate for that person, in which case a change to glucose measurement is warranted.

Laboratory or point of care measurement?

Several instruments for rapid point of care testing of HbA_1c are available for the monitoring of patients known to have diabetes, but most of these analysers do not perform sufficiently well to be used for diagnostic purposes.9 If they are used, the analytical quality needs to be able to match that of clinical laboratories.6

Outcome

This patient had his HbA_1c measured and found to be 44 mmol/mol (6.2%). As this placed him into the category of being at increased risk of diabetes, he was given lifestyle and dietetic advice and had an assessment of other cardiovascular risk factors. He was asked to report any worsening in his symptoms of diabetes should this happen before the annual HbA_1c measurements now planned.