Definition, classification and diagnostics of diabetes mellitus

Explaining introduction

Diabetes is one of the major health burdens throughout the world and belongs to the four priority noncommunicable diseases. Globally, it is estimated that 422 million adults were living with diabetes in 2014 which is almost four times as many as in 1980, and the global prevalence nearly doubled since then. According to the results of the current study by the Robert Koch Institute, diabetes was diagnosed in 7.2% of all adults between 18 and 79 years in Germany which is a 2% increase in prevalence compared to the “Bundes-Gesundheitssurvey 1998”. Moreover, unrecognized diabetes has to be supposed in 2% of all adults. Up to 95% of these are suffering from type 2 diabetes which occurs more often with increasing age and is associated with higher body weight and insufficient physical activity.

Diabetes mellitus that is unrecognized or untreated over longer time periods or is insufficiently treated is associated with increased risk of cardiovascular disease, kidney dysfunction, blindness and foot amputation. As reported by the Emerging Risk Factors Collaboration who analyzed 123,205 deaths among 820,900 people in 97 prospective studies, the life expectancy is drastically affected, i.e. a 50-year-old male diabetes patient has a 5.8-year reduced life span compared to a 50-year-old man without diabetes. In women, the reduction is 6.5 years in this age-group. In addition, in the elderly, hypoglycemia has been recognized as another emerging complication pointing to the importance of accurately and tightly controlled blood glucose levels in these patients.

The present recommendation is supposed to provide the latest consensus in diabetes diagnosis to improve patient care and aid the practitioners’ daily work.

Definition of diabetes mellitus

Diabetes mellitus is a general term for a group of metabolic disorders with the main feature of chronic hyperglycemia. It results from either impaired insulin secretion or impaired insulin efficacy or, most often, both.

Diagnostic criteria for diabetes mellitus

• Random plasma glucose value of ≥200 mg/dL (≥11.1 mmol/L) or

• Fasting plasma glucose value of ≥126 mg/dL (≥7.0 mmol/L) or

• 2-h oral glucose tolerance test (oGTT) value in venous plasma ≥200 mg/dL (≥11.1 mmol/L)

• glycated hemoglobin (HbA_1c) ≥6.5% (≥48 mmol/mol Hb)

Impaired fasting glucose values

Impaired fasting glucose (IFG) for the interval of fasting glucose from 100 to 125 mg/dL (5.6–6.9 mmol/L) in venous plasma.

Impaired glucose tolerance

Impaired glucose tolerance (IGT) corresponds to a 2-h plasma glucose value in oGTT in the interval from 140 to 199 mg/dL (7.8–11.0 mmol/L) with fasting glucose values <126 mg/dL (<7.0 mmol/L).

IFG and IGT are also present in many people with a glucose utilization disorder.

Diagnostic approach

The recommended diagnostic procedure is shown in Figure 1 and the differential diagnostic approach criteria are shown in Table 1.

Figure 1:

Diagnostic approach for diagnosing diabetes.

Only quality-assured laboratory methods may be used when measuring venous plasma glucose and HbA_1c in diabetes diagnostics. This is defined in the guidelines published by the ‘Richtlinie der Bundesärztekammer zur Qualitätssicherung laboratoriumsmedizinischer Untersuchungen (Rili-BAEK)” (Guideline of the German Medical Association on Quality Assurance in Medical Laboratory Examinations) as standard for both central laboratories and point-of-care testing (POCT). Participation in external quality assessment (EQA) schemes has not been compulsory for POCT methods used in practices in Germany. If POCT systems are approved for diagnostic purposes by the manufacturer, the successful participation in EQA schemes, however, is mandatory before they can be used in diagnostics. Currently, the gold standard for diabetes diagnosis is the measurement of glucose in venous plasma.

Procedures if measurement results are close to the diagnostic criteria levels

When using the fasting glucose value, a fasting time of 8–12 h is essential. The guidelines for performing an oGTT must be followed (Table 2). Using the HbA_1c value for diagnosis is currently not recommended, in particular, because the allowed deviation for external quality control tests is ±18% to date in Germany. This value will be reduced to ±8% in the next years in the Rili-BAEK, then using HbA_1c as a diagnostic criterion will improve significantly. The sensitivity of the laboratory tests for diagnosing diabetes is specified below in ascending order in relation to the oGTT, i.e. an oGTT should be performed to rule-out diabetes if the HbA_1c values and fasting glucose values lie closely below the diagnostic criteria.

How should the diagnostic value of a single measurement be assessed in consideration of the variability of measurement results?

For measurement results of these measurands, the question is whether the deviation from the diagnostic criterion (or cut-off value) exceeds this value to such an extent [i.e. larger than the minimal difference (see below)] that this can clearly be considered elevated. If this is the case, one individual measurement is sufficient to confirm diabetes diagnosis. For two values diverging the cut-off value (above and below), the American Diabetes Association (ADA) recommends taking the higher value. This value should be repeated and becomes the deciding factor for the diagnosis. If clinically necessary, verification should be performed in time, e.g. after 3 or 6 months. The procedure for diagnosing diabetes (as published by the ADA 2018) is as follows: “If a parameter is used and then repeated to confirm the diagnosis of diabetes, it must be ensured that each blood sample was standardized and comparably processed”. How well this is realized for plasma glucose is not simply verifiable. If the diabetes diagnosis is based on an HbA_1c measurement, the confirmation measurement with the same measurand is not advisable. Due to analytical differences between laboratories the HbA_1c measurement is currently not very well reproducible. Additionally, a “false” value may be obtained repeatedly due to the same patient-specific influencing factors. Independent of the measurand used for diabetes diagnosis, the result may be incorrect resulting from patient-specific influencing factors and/or insufficient measurement accuracy. A questionable diabetes diagnosis should therefore be confirmed using the other measurand (i.e. either glucose or HbA_1c) in order to reduce interference or influencing factors. A measurement result which is used as a basis for diagnosis should be confirmed so that the diagnosis is made on the basis of confirmed values. It can be confirmed either by analysing a new blood sample using the same measurand (e.g. within 14 days) or by using one of the three measurands described above. If, during a second determination of the same laboratory test, there is a discrepancy in the value with regard to the cut-off value, one of the alternatives should be used for determination. If there are disparities in the results with regard to the diagnostic criterion in two different measurands, the higher value should be confirmed. If the values are close to the limit values, they should be monitored within 3–6 months again.

Pre-analytics of glucose measurement

Proper pre-analytic handling of the blood sample is crucial. Suitable blood collection tubes must be used to completely inhibit glycolysis in the collected blood. The addition of citrate and fluoride is necessary as fluoride alone is insufficient. The glycolytic inhibitor tubes for blood collection currently available on the German market exhibit different handling problems (Table 3). One alternative recommendation for tubes without glycolytic inhibitors is to centrifuge the sample as soon as possible after blood collection. If a period of 30 min to centrifugation is exceeded, samples should be discarded due to the occurence of glycolysis. After centrifugation, the resulting plasma supernatant must be separated from the blood cells. This occurs during centrifugation using a gel (gel tubes) or mechanical separators. It is also possible to pipette off the plasma supernatant immediately after centrifugation. Diligent and optimal pre-analytical handling of the blood collection tubes can result in a higher rate of diabetes diagnosis in practice and should not be considered over-diagnosing; however, the cut-off values used below may require adjustment and should be verified with corresponding studies.

HbA_1c for diagnosis purposes

Since 2010, the German Diabetes Association (“Deutsche Diabetes Gesellschaft”, DDG) has recommended the use of the HbA_1c value for diabetes diagnosis (see the statement on the DDG homepage). This was made possible by improvements in measurement accuracy resulting from international standardization of HbA_1c measurement methods. Simultaneously, epidemiological studies in recent years have shown that the specificity of an HbA_1c value of ≥6.5% or >48 mmol/mol is sufficiently high to diagnose diabetes with a satisfactory level of certainty. At the same time, the sensitivity of an HbA_1c value of <5.7% (<39 mmol/mol Hb) is sufficiently high to rule out the diagnosis of diabetes. For patients with HbA_1c values in the range of 5.7 to <6.5% (39 to <48 mmol/mol Hb) or with a high clinical risk (see Screening), the diagnosis of diabetes and its early stages can only be excluded by measuring plasma glucose in accordance with the usual criteria including an oGTT. The HbA_1c value is not suitable for diagnosing diabetes if values can be expected to be influenced or falsified (Table 4; see Practical Recommendation Glucose Monitoring and Control Testing for details on methodology). It is also important to note that regardless of successful standardization, measurement accuracy of HbA_1c can vary considerably depending on the measurement method. In our opinion, this problem significantly limits the exclusive use of HbA_1c for the diagnosis of diabetes; for more details, see the practical recommendations next to Table 4 in the legend to Figure 1. In particular, the increase of HbA_1c that is associated with increasing age independent of diabetes, which can be up to an absolute value of 0.4–0.7% (4–8 mmol/mol Hb) constitutes another limitation in addition to differences due to methodology for using HbA_1c to diagnose diabetes especially in the order below 7.0% (53 mmol/mol Hb).

Quality control checks

Internal quality control must be performed every working day with suitable control material. Successful participation in EQA is required once per quarter. This applies to all laboratory systems as well as to POCT “unit use” systems (single test strips or cuvettes as per the definition of Rili-BAEK) which are designated appropriate for diagnosis by the manufacturer.

Minimal difference

In order to meet the clinical requirements, the analytical variability of the absolute values at decision limits should be specified. The “minimal difference (MD)” is a simple tool to demonstrate the significance of random errors to the user and is calculated from the standard deviation (SD) (MD=2×SD) (Figure 2). The MD gives specific concentrations as absolute values to specify if a measurement result differs from a cut-off value with diagnostic relevance. The MD should not be larger than 12.6 mg/dL (0.7 mmol/L) for a fasting glucose limit value of 126 mg/dL (7.0 mmol/L). Accordingly, for the HbA_1c cut-off value of 48 mmol/mol Hb, the MD should not be larger than 1.9 mmol/mol Hb. A statement on the subject of MD can be found on the DDG homepage and will be published separately soon.

Figure 2:

Minimal difference, given in the unit of glucose determination (mg/dL or mmol/L) for the considered diagnostic cut-off value depending on the coefficients of variation.

If the measured values lie in the overlapping areas of the inverted triangles, the diagnostic limit values cannot be differentiated from each other and the measured values cannot be used for diagnosis.

Screening

For primary screening for diabetes either a “Diabetes Risk Test” (http://www.dife.de/diabetes-risiko-test/) or occasional measurement results using venous plasma is recommended. In the case of elevated risk scores detected by this questionnaire, documented cardiovascular disease, presence of excess weight with additional risk factors such as hypertension, dyslipidemia (increased triglyceride values or low HDL cholesterol value) or a positive family history of type 2 diabetes in first-degree relatives, gestational diabetes or polycystic ovarian (PCO) syndrome or non-alcoholic fatty liver disease proceed as described in Figure 1. Alternatively, the FINDRISK questionnaire can also be used (https://www.diabetesstiftung.de/findrisk).

Gestational diabetes

The cut-off values for oGTT stated in Table 5 are based on the results of the hyperglycemia and adverse pregnancy outcome (HAPO) Study. They differ only slightly from the previously used decision limits. However, now already one value exceeding the decision limit suffices to confirm the diagnosis while previously two elevated values were required.

Internet addresses

http://www.deutsche-diabetes-gesellschaft.de

• Current version of evidence-based guidelines

• Information systems on diabetes

Summary

The present recommendation summarizes the current knowledge and state of the art for the diagnosis of diabetes mellitus. With emphasis on well-described but often neglected pitfalls like measurement imprecision, pre-analytical considerations of glucose measurement and limitations of HbA_1c assessment, this work is intended to improve patient care and to draw attention of physicians to potential drawbacks in diabetes diagnosis.