Diabetes and pre-diabetes
Type 2 diabetes (T2DM) is one of the world’s most common medical conditions. The prevalence of diabetes is estimated to rise globally, from 8% in 2019 to 10% in 2045 with T2DM accounting for about 90% of all cases of diabetes [1]. In Sweden it is estimated that 500 000 people, about 4% of the population, have diabetes and that one third of all individuals with T2DM are unidentified [2]. This indicates that reliable screening and testing needs to be further researched to identify individuals at risk of developing diabetes. If these individuals who are at risk of developing T2DM are detected in time the progression of the condition can be halted through lifestyle interventions [3-6].
Clinically used tests for diagnosing diabetes include fasting plasma glucose (fP-glucose), oral glucose tolerance test (OGTT) and Glycated haemoglobin (HbA1c). A fasting plasma glucose is a simple venous or capillary glucose test performed on a fasting patient. Alternatively, an OGTT can be performed. In an OGTT a fasting patient will drink a solution of glucose and water, plasma glucose is measured at minutes 0 and 120. HbA1c value is a way to estimate long-term blood glucose levels; it represents the average blood sugar levels over the past three months. A big advantage of HbA1c testing over the other two is that it is a quick and simple test that do not require the patient to be fasting. HbA1c values are, in contrast to OGTT and fasting glucose, not affected by stress or nicotine/caffeine intake. Drawbacks of HbA1c testing include differing levels of glycation in different ethnic groups leading to it poorly reflecting levels of hyperglycaemia in some groups. Studies conducted on US populations show higher levels of HbA1c in black Americans than white, even after adjusting for fasting plasma glucose [7]. A Canadian study shows lower sensitivity for HbA1c testing to detect pre-diabetes and diabetes in Asian populations compared to Caucasians [8]. OGTT is out of the three the most reliable way of diagnosing diabetes and is a good way of detecting abnormal glucose tolerance, especially in asymptomatic patients. Using only fasting plasma glucose up to 30% of undiagnosed diabetics will remain undetected. The obvious drawback of OGTT is the fact that it is a time-consuming test, both for the patient and the clinic. It can also cause discomfort and nausea, especially for undiagnosed diabetics where hyperglycaemia may occur.
Risk factors for developing T2DM include hypertension, hyperlipidaemia, obesity and being born in the Middle East, Asia or in Africa [9-11]. In particular, individuals originating from Middle Eastern countries, one of the largest immigrant groups in Sweden, are at elevated risk of developing T2DM [10, 12]. Pre-diabetes is another important risk factor. It is a term used to conveniently identify individuals with impaired glucose metabolism and it is estimated that 15-30% of individuals with pre-diabetes will develop diabetes within five years [12]. According to Stockholm’s Diabetes Prevention Program (SDPP) the prevalence of pre-diabetes is four and seven percent for 35-55-year-old women and men respectively.
Following WHO (World Health Organisation) recommendations [13], pre-diabetes is defined by Swedish guidelines as either [14]: 1) IFG (impaired fasting glucose) - fP-glucose of 6.1-6.9 mmol/L and 2) IGT (impaired glucose tolerance) - 75g OGTT (oral glucose tolerance test) with a venous glucose of 7.8-11.0 mmol/L after 2 hours.
In accordance to WHO guidelines, HbA1c levels are not used in Sweden to define pre-diabetes. However, an HbA1c of 42-47 mmol/mol can be used to define an “at risk” population that need to be further tested with OGTT/FPG [13, 14]. In contrast to WHO guidelines which only include the usage of OGTT and FPG to define pre-diabetes, ADA (American Diabetes Association) additionally use HbA1c levels to define pre-diabetes [15]. The cut off values and criteria also vary considerably between the two organisations. ADA defines pre-diabetes as the following: OGTT result of 7.8-11.0 mmol/mol, FPG result of 5.6-6.9 mmol/mol, and HbA1c levels of 39-47 mmol/mol. While the thresholds for OGTT are the same for both WHO and ADA, the cut off for FPG levels is lower by ADA guidelines. The HbA1c cut off value is also lower for ADA then the “at risk” levels defined by WHO, 39-47 mmol/mol compared to 42-47 mmol/mol. It is unclear which criteria are best suited for identifying individuals with pre-diabetes, the varying diagnostic criteria are however important to regard when comparing incidence and prevalence rates between studies [14, 15].
Lifestyle changes in individuals with pre-diabetes have been shown to be successful in lowering the risk of developing T2DM [5, 6, 16-21]. Intervention during prediabetic stages can normalize the blood levels of glucose and significantly reduce the risk of T2DM in these patients. American studies show that the implementation of programs promoting lifestyle changes in populations at high risk for developing T2DM is a cost-effective way of preventing T2DM and thereby reducing future healthcare costs. If these results are transferable to a Swedish population is yet to be investigated [4, 22].
A Swedish study published in 2015 showed that screening for a HbA1c value of ≥42 mmol/mol only detected 16% of patients with IGT (diagnosed by OGTT). Meanwhile, the mean HbA1c levels for patients with IGT was 36.3 mmol/mol and for patients with IFG was 37.9 mmol/mol. However, for patients with an HbA1c value of >42 mmol/mol the specificity for IGT was 0.94. This study was conducted on a randomized population from the two smaller Swedish communities, Vara and Skövde. The final population consisted of 573 participants of which less than 10% were of non-European origin [23]. Another Swedish study using four cohorts including patients with Middle-Eastern ancestry and Swedish origin concluded that an HbA1c is insensitive screening tool: third of those with diabetes were detected by HbA1c≥48 mmol/mol, a third of those with pre-diabetes were detected by HbA1c≥39 mmol/mol and a HbA1c≥42 mmol/mol would detect only 15% of those with pre-diabetes [24].Other studies have also shown a disparity between HbA1c testing and OGTT in the identification of individuals with pre-diabetes and diabetes [23, 25, 26]. The previously described study was conducted on a population mainly consisting of individuals born in Europe; disparities in HbA1c levels between ethnic groups have been found but are not well studied. A need for individualised HbA1c cut off and target values for different ethnicities therefore seems reasonable [8, 27].
HbA1c testing is not recommended as screening for pre-diabetes in Sweden as cut off values with adequate specificity and sensitivity are not yet determined, finding such would provide great benefits in the screening of pre-diabetes since HbA1c levels are easily tested compared to OGTT and fasting glucose levels. Because of the variability of HbA1c levels in different ethnicities specific cut off values for different groups need to be determined in order to achieve optimal sensitivity and specificity. In order for HbA1c testing to be used as a clinically relevant screening tool at least 70-80% of patients with diabetes/pre-diabetes should be found. While studies comparing HbA1c and OGTT previously have been conducted on Swedish populations, no studies have focused on the relation between HbA1c and OGTT/ in populations of predominantly foreign-born people in Sweden. Studies investigating differences in HbA1c accuracy between Swedish-born and foreign-born individuals are yet to be conducted. This study will attempt to fill this knowledge gap and possibly set the basis for future studies to find individualised cut off values for different groups.
The aim of this study was to compare the diagnostic accuracy of HbA1c in detecting individuals with abnormally elevated blood glucose levels between foreign-born and Swedish-born primary healthcare patients. The secondary aim was to approximate appropriate HbA1c cut off values for the different populations to yield better sensitivity and specificity.