Interpretation of HbA1c in primary care and potential influence of anaemia and chronic kidney disease: an analysis from the Copenhagen Primary Care Laboratory (CopLab) Database.

AIMS: To investigate, in a large population in primary care, the relationship between fasting plasma glucose and HbA1c measurements, as well as the clinical implications of anaemia or chronic kidney disease for the interpretation of HbA1c values. METHODS: From a primary care resource, we examined HbA1c and fasting plasma glucose as well as haemoglobin and estimated GFR. We stratified observations by chronic kidney disease stage and anaemia level. The estimation of the mean fasting plasma glucose level from HbA1c alone, and from HbA1c , haemoglobin and estimated GFR, respectively, was evaluated. RESULTS: In 198 346 individuals, the fasting plasma glucose-HbA1c relationship mimicked the regression described in the A1c-Derived Average Glucose (ADAG) study, which was based on average capillary and interstitial glucose. The fasting plasma glucose-HbA1c relationship was unaffected in mild to moderate chronic kidney disease and in mild to moderate anaemia. The correlation changed only in severe hyperglycaemia and concurrent severe anaemia or when estimated GFR was <45 ml/min/1.73m², so that glucose concentration was underestimated by HbA1c in anaemia and overestimated in chronic kidney disease. The prevalence of estimated GFR <30 ml/min/1.73m² was 0.82%, while the prevalence of haemoglobin <81 g/l (5.0 mmol/l) was 0.11%. CONCLUSIONS: The relationship between fasting plasma glucose and HbA1c mimics that of the people with diabetes included in the ADAG study. Mild to moderate anaemia and CKD do not have a significant impact on the interpretation of HbA1c as a marker of retrograde glycaemia. Hence, it seems justified to use HbA1c without adjustment in primary care.

Motivation, effort and life circumstances as predictors of foot ulcers and amputations in people with Type 2 diabetes mellitus.

AIM: To investigate the predictive value of both patients' motivation and effort in their management of Type 2 diabetes and their life circumstances for the development of foot ulcers and amputations. METHODS: This study was based on the Diabetes Care in General Practice study and Danish population and health registers. The associations between patient motivation, effort and life circumstances and foot ulcer prevalence 6 years after diabetes diagnosis and the incidence of amputation in the following 13 years were analysed using odds ratios from logistic regression and hazard ratios from Cox regression models, respectively. RESULTS: Foot ulcer prevalence 6 years after diabetes diagnosis was 2.93% (95% CI 1.86-4.00) among 956 patients. General practitioners' indication of 'poor' vs 'very good' patient motivation for diabetes management was associated with higher foot ulcer prevalence (odds ratio 6.11, 95% CI 1.22-30.61). The same trend was seen for 'poor' vs 'good' influence of the patient's own effort in diabetes treatment (odds ratio 7.06, 95% CI 2.65-18.84). Of 1058 patients examined at 6-year follow-up, 45 experienced amputation during the following 13 years. 'Poor' vs 'good' influence of the patients' own effort was associated with amputation (hazard ratio 7.12, 95% CI 3.40-14.92). When general practitioners assessed the influence of patients' life circumstances as 'poor' vs 'good', the amputation incidence increased (hazard ratio 2.97, 95% CI 1.22-7.24). 'Poor' vs 'very good' patient motivation was also associated with a higher amputation incidence (hazard ratio 7.57, 95% CI 2.43-23.57), although not in fully adjusted models. CONCLUSIONS: General practitioners' existing knowledge of patients' life circumstances, motivation and effort in diabetes management should be included in treatment strategies to prevent foot complications.

Structured personal care of type 2 diabetes: a 19 year follow-up of the study Diabetes Care in General Practice (DCGP).

AIMS/HYPOTHESIS: This study is a 19 year observational follow-up of a pragmatic open multicentre cluster-randomised controlled trial of 6 years of structured personal diabetes care starting from diagnosis. METHODS: A total of 1,381 patients aged ≥ 40 years and newly diagnosed with type 2 diabetes were followed up in national registries for 19 years. Clinical follow-up was at 6 and 14 years after diabetes diagnosis. The original 6 year intervention included regular follow-up and individualised goal setting, supported by prompting of doctors, clinical guidelines, feedback and continuing medical education (ClinicalTrials.gov NCT01074762). The registry-based endpoints were: incidence of any diabetes-related endpoint; diabetes-related death; all-cause mortality; myocardial infarction (MI); stroke; peripheral vascular disease; and microvascular disease. RESULTS: At 14 year clinical follow-up, group differences in risk factors from the 6 year follow-up had levelled out, although the prevalence of (micro)albuminuria and level of triacylglycerols were lower in the intervention group. During 19 years of registry-based monitoring, all-cause mortality was not different between the intervention and comparison groups (58.9 vs 62.3 events per 1,000 patient-years, respectively; for structured personal care, HR 0.94, 95% CI 0.83, 1.08, p = 0.40), but a lower risk emerged for fatal and non-fatal MI (27.3 vs 33.5, HR 0.81, 95% CI 0.68, 0.98, p = 0.030) and any diabetes-related endpoint (69.5 vs 82.1, HR 0.83, 95% CI 0.72, 0.97, p = 0.016). These differences persisted after extensive multivariable adjustment. CONCLUSIONS/INTERPRETATION: In concert with features such as prompting, feedback, clinical guidelines and continuing medical education, individualisation of goal setting and drug treatment may safely be applied to treat patients newly diagnosed with type 2 diabetes to lower the risk of diabetes complications.

Amputations and foot ulcers in patients newly diagnosed with type 2 diabetes mellitus and observed for 19 years. The role of age, gender and co-morbidity.

AIMS: To determine the prevalence of foot ulcers and the incidence of amputations in patients with Type 2 diabetes observed for 19 years after diagnosis. We investigated the role of gender, age and co-morbidities. METHODS: From the Diabetes Care in General Practice study, 1381 patients were included and examined at diabetes diagnosis, at 6 years and at 14 years after diagnosis. Register-based follow-up was for 19 years. Foot ulcers and amputations were related to gender, age and co-morbidities by odds and hazard ratios from logistic and Cox regression models, respectively. RESULTS: The incidence of any amputation and major amputation was 400 (95% CI 307-512) and 279 (95% CI 203-375) per 100,000 patient-years, respectively. At the three observation points, the foot ulcer prevalences were 2.76% (95% CI 1.89-3.63), 2.93% (95% CI 1.86-4.00) and 4.96% (95% CI 3.10-6.82). Multivariate analyses showed associations between foot ulcers and peripheral neuropathy, peripheral arterial disease, male gender, retinopathy and myocardial infarction. After multivariate adjustment, significant predictors (hazard ratio; 95% CI) of any amputation were peripheral neuropathy (hazard ratio 2.09; 95% CI 1.19-3.69), peripheral arterial disease (hazard ratio 3.43; 95% CI 1.65-7.12), microalbuminuria (hazard ratio 2.11; 95% CI 1.21-3.67), retinopathy (hazard ratio 6.42; 95% CI 2.59-15.90), impaired vision (hazard ratio 6.92; 95% CI 2.35-20.38) and male gender (hazard ratio 2.40; 95% CI 1.31-4.41). For women, the risk of amputation increased with age, but for men the risk was higher when diagnosed with diabetes at a younger age. CONCLUSIONS: Despite improved treatment regimens, the incidence of amputations is still high in this population-based patient sample. Men diagnosed with diabetes before age 65 years and patients with diabetes-related co-morbidities are at particularly high risk of foot ulcers and amputations.

Weight history of patients with newly diagnosed Type 2 diabetes.

AIMS: To estimate and illustrate how the 10 years of weight change immediately preceding diabetes diagnosis vary with weight at the age of 20 years and with socio-demographic variables, risk factors and comorbidities at diagnosis. METHODS: Data were from a population-based cohort of 1320 persons newly diagnosed with diabetes aged > or = 40 years. Patients' weight at diagnosis was measured by the doctor, while patients recalled their weight approximately 1, 5 and 10 years prior to diagnosis and at age 20 years. RESULTS: Median weight gain from age 20 years to diabetes diagnosis at median age 65.3 years was 14.7 kg (interquartile range 6.0-23.0). Women gained weight more than men, and the lower the weight at age 20 years, the greater the weight gain. The average weight gain from 10 years prior to diabetes diagnosis until diagnosis, however, was only 1 kg and decreased markedly with age. These 10 years of weight change were also associated with sex and the following baseline characteristics: diagnostic plasma glucose, urinary glucose, urinary albumin, fasting triglycerides, systolic blood pressure, smoking habits, and presence of diabetic retinopathy. CONCLUSIONS: The results add to the evidence that it is important to advise young patients in particular, especially women, who have gained and sustained considerable weight to curb this upward weight trend in order to prevent the development of diabetes.

Peripheral vascular disease is associated with reduced glycosuria in newly diagnosed type 2 diabetic patients.

OBJECTIVES: We examined whether the finding of glycosuria and its level in themselves give information of clinical relevance, apart from being an unreliable indicator of glycemic control. METHODS: Subjects were a population-based sample of 1,284 newly diagnosed type 2 diabetic patients. Median age was 65.2 years. Urinary glucose concentration (UGC) was determined quantitatively in a freshly voided morning urine specimen. RESULTS: The over-all prevalence of peripheral vascular disease (PVD) was 16.5%. Bivariately, high values of UGC were associated with low prevalence of PVD (p<0.001, chi2-test). The predictive value of PVD--together with HbA1c, glomerular filtration rate (GFR) and 10 other possible predictors--was confirmed in a logistic regression analysis with glycosuria (Y/N) as outcome variable (p=0.0004). CONCLUSION: Surprisingly, type 2 diabetic patients with PVD tend not to have glycosuria as compared to patients without PVD. PVD may be indicative of generalized atherosclerotic lesions in the major vessels, including the renal arteries. This could lead to a lowering of GFR and thereby of the amount of glucose filtered. Assuming no, or only a minor direct effect of PVD on tubular function, this would lead to an increased renal threshold for glucose in patients with PVD.

Five-year all-cause mortality of 1323 newly diagnosed middle-aged and elderly diabetic patients. Data from the population-based study, diabetes care in general practice, Denmark.

The 5- to 6-year all-cause mortality is analyzed in 1323 newly diagnosed diabetic patients aged 40 years or over. The median age at diagnosis is lower for men (63.6 years) than for women (67.5 years), but more men (24.7%) than women (20.0%) have died (p = 0.04). This male excess mortality can be attributed mainly to the 60- to 79-year-old men. With increasing diabetes duration, both male and female diabetic patients exhibit an increasing excess mortality in comparison with the Danish population. For men, this excess mortality becomes statistically significant 4 years after diagnosis for the 40- to 59-year-old patient and 6 years after diagnosis for the 60- to 79-year-old patient. For women and very old men, no statistically significant excess mortality is observed. After 2-4 years, however, there is a tendency for the survival curve of 40- to 79-year-old women to separate from that of the Danish female population to show an excess mortality. In this population-based study, the disadvantageous mortality experience of even newly diagnosed diabetic patients is clearly demonstrated.

Microalbuminuria in non-insulin-dependent diabetes.

According to international consensus, microalbuminuria is defined as an elevated urinary albumin excretion rate (UAER) of 20-200 micrograms/min, which is below the proteinuric range. Nephropathy is a major complication in IDDM, seen in about 30% of patients after many years of diabetes. Increasing microalbuminuria is an excellent marker of subsequent nephropathy in these patients. End-stage diabetic nephropathy is also important in NIDDM, but in most Western countries this serious complication eventually develops in only 5 to 10% of cases, whereas the majority of patients die before this from cardiovascular disease. In completely healthy individuals there is no clear correlation between age and UAER, at least up to about 70 years of age. The mean excretion rate is around 5 micrograms/min, with a considerable range, but excretion only rarely exceeds 15 micrograms/min. In population studies among middle-aged and elderly individuals, higher values are seen. In newly diagnosed NIDDM about 40% of patients show an excretion rate above 15-20 micrograms/min. There is a significant but not precise correlation between albumin excretion rate and glycemic control, and usually UAER is reduced by standard antidiabetic treatment. In a considerable number of patients, high values cannot be reduced. In the course of NIDDM about 20-30% of patients show microalbuminuria. In patients with known diabetes, microalbuminuria is related not only to subsequent diabetic proteinuria, but even more strongly to early death, mainly from cardiovascular disease. Even slight microalbuminuria (15-40 mg/l in early morning urines) is clearly associated with increased mortality. In subjects with newly detected elevated blood glucose (by screening) microalbuminuria also predicts early mortality. The mechanisms are not established, but several arteriosclerosis-related risk factors are seen more frequently in patients with microalbuminuria, e.g. lipid abnormalities, elevated systolic blood pressure (BP), hemostatic measures, as well other markers of cardiovascular disease. Usually there is a significant but not precise correlation between BP and UAER in groups of patients throughout the course of diabetes. New studies document that also in the elderly background population microalbuminuria is a significant risk factor for early death, maybe even stronger than the established risk markers, which thus may be confounded with the presence of microalbuminuria.

Discrepancy in HbA1c measurements performed at different local laboratories and at a selected central reference laboratory.

As participants in a general practice intervention study, 66 patients had their HbA1c measured both at a local and at a selected central reference laboratory. A discrepancy in the results was observed, as 97% of the results measured locally were lower than the centrally determined results. Bias (as calculated from mean value of measured HbA1c) between local laboratories and the central laboratory was measured to -1.47% HbA1c. A bias of this magnitude gave "problems" both to the general practitioners, patients and laboratories. To reduce the "problems" a bias of 0.5% HbA1c is estimated to be acceptable. But, to avoid these "problems" totally, a bias of 0.25% HbA1c is estimated to be the highest allowed bias. For HbA1c, a control system for both control of method standardisation and for specificity is described.

[Screening for alcohol overconsumption in general practice. Experiences of general practitioners with a patient questionnaire]. / Screening for storforbrugere af alkohol i almen praksis. Alment praktiserende laegers erfaring med et patientspørgeskema.

INTRODUCTION: We investigated to which degree a sample of 143 general practitioners in the County of Copenhagen would screen their patients for problem drinking by using The Alcohol Use Disorders Identification Test (AUDIT). Furthermore, among users of AUDIT, we aimed to describe the doctors' perception of using it. METHODS: Eighty-one out of the 143 doctors requested AUDIT. However, after they had had the possibility of using AUDIT, only 38 had handed an AUDIT to at least one patient. These 38 doctors were asked to answer a questionnaire on which this study is based. RESULTS: Thirty-two percent (12/38) of the doctors handed out an AUDIT in more than 14 days, and 21% (8/38) gave at least 100 patients an AUDIT. The general practitioners worked a median of 20 days in their practice during the study period. Only 14% (5/36) would screen all their patients in the future, and 42% (15/36) only when they suspected problem drinking. Sixty-four percent (22/34) of the doctors stated that handing all patients an AUDIT was much too time-consuming, 50% (17/34) stated that financial incentives are necessary, and 53% (18/34) questioned whether the patients wanted an AUDIT. Sixty-six percent (23/35) of the doctors judged that they had improved in detecting patients with alcohol related problems. CONCLUSION: The participating general practitioners were not interested in handing all patients an AUDIT. Major barriers were lack of time and financial incentives and furthermore the doctors questioned whether the patients wanted an AUDIT. However, half of the doctors would use AUDIT for certain patients, especially when they suspected problem drinking.

[Randomized controlled trial of structured, individualized treatment of type 2 diabetes mellitus. The project of Diabetes Care in General Practice]. / Randomiseret kontrolleret undersøgelse af struktureret, individualiseret behandling af type 2-diabetes mellitus. Projektet Diabetesomsorg i almen praksis.

INTRODUCTION: We assessed the effect of a multifaceted intervention directed at general practitioners to improve type 2 diabetes care. MATERIALS AND METHODS: Three hundred and eleven Danish practices with 474 general practitioners were randomised to structured personal care (intervention group) or routine care (comparison group). Of 970 surviving patients (aged 40+ years) diagnosed with diabetes in 1989-1991, 874 (90.1%) were assessed after 6 years. Intervention comprised regular follow-up and individualized goal-setting, supported by reminders to doctors, clinical guidelines, feed-back, and continuing medical education. RESULTS: Predefined non-fatal outcomes and mortality were the same in both groups. The following risk factor levels were lower in the intervention patients than in the comparison patients: fasting plasma glucose (7.9 vs 8.7 mmol/l, medians, P = 0.0007), haemoglobin A1c (8.5 vs 9.0%, P < 0.0001, normal range 5.4-7.4%), systolic blood pressure (145 vs 150 mmHg, P = 0.0004), and cholesterols (6.0 vs 6.1 mmol/l, P = 0.029, baseline-adjusted). Both groups had sustained a weight loss since diagnosis (2.6 vs 2.0 kg). Metformin was the only drug used more frequently in the intervention group (24 vs 15%). Intervention doctors arranged more follow-up consultations, referred fewer patients to diabetes clinics, and were more optimistic in their goal-setting. DISCUSSION: In primary care, individualized goal-setting with educational and surveillance support may for at least six years bring risk factors of patients with type 2 diabetes to a level that in other trials has been shown to reduce diabetic complications, but without adverse weight gain.

Patients newly diagnosed with clinical type 2 diabetes mellitus but presenting with HbA1c within normal range: 19-year mortality and clinical outcomes.

AIMS: To investigate whether long-term mortality or clinical outcomes differed between patients diagnosed with type 2 diabetes mellitus and presenting with HbA1c within or above normal range at time of diagnosis. METHODS: Data were from a population-based sample of 1136 individuals with newly diagnosed type 2 diabetes mellitus. The diagnosis was confirmed with a single fasting whole blood/plasma glucose ≥7.0/8.0mmol/l. The median time from day of diagnosis until end of follow up was 18.8years. Patients were grouped according to normal HbA1c and elevated HbA1c at diagnosis. The effect of elevated HbA1c on a number of clinical outcomes and all-cause mortality was assessed in Cox regression models. RESULTS: At diagnosis, 97 patients (8.5%) had an HbA1c level within normal range. Age (mean (SD)) at diagnosis was 64.5 (11.5) years. Both unadjusted and adjusted hazard ratios for the effect of HbA1c on mortality and other outcomes were not statistically significant. CONCLUSIONS: Patients who are diagnosed with type 2 diabetes mellitus by means of elevated fasting whole blood/plasma glucose but have HbA1c within reference range at diagnosis do not seem to have a relatively benign long-term clinical course. Therefore new diagnostic procedures should preferably be able to identify these individuals.

Changes in patient weight and the impact of antidiabetic therapy during the first 5 years after diagnosis of diabetes mellitus.

AIMS/HYPOTHESIS: It is generally thought difficult for type 2 diabetic patients to lose weight. We monitored changes in patients' weight during the first 5 years after diabetes diagnosis in relation to initiation of antidiabetic treatment. SUBJECTS AND METHODS: Data from 711 newly diagnosed diabetic patients aged 40 or over were analysed with a random-effect linear-regression model. Patients were included consecutively from a well-defined patient list in general practice. RESULTS: In 245 patients whose only treatment was advice on diet, an initial weight loss of 6 to 7 kg was largely maintained over 5 years. Patients receiving metformin (n=86) or sulfonylureas (n=330) maintained an average weight loss of 2 to 4 kg that was dependent on age and sex. Patients' weight did not change on initiation of treatment with sulfonylureas or metformin. Over 5 years, median HbA(1c) increased from 7.0 to 7.8% (reference range 5.4-7.4%) in the diet-alone group. HbA(1c) was approximately 1 percentage point higher for most of the other treatment groups. CONCLUSIONS/INTERPRETATION: In newly diagnosed type 2 diabetic patients, long-term weight loss was common and weight loss was not affected by sulfonylurea treatment. The measurements in the study are taken from treatment results achieved in the general population of diabetic patients, who are rarely treated in secondary care and seldom the subject of research; the results thus indicate that weight reduction is a practicable treatment in diabetic patients.

Symptoms, signs and complications in newly diagnosed type 2 diabetic patients, and their relationship to glycaemia, blood pressure and weight.

AIMS/HYPOTHESIS: To document the prevalence of typical diabetic symptoms, signs and complications in the diagnosis of type 2 diabetes mellitus, examine their pre-diagnostic duration, and analyse associations with glycaemic level, blood pressure (BP), and weight. METHODS: An epidemiological population-based study of 1137 Danish patients with type 2 diabetes newly diagnosed by general practitioners (GPs). GPs and patients together filled in a questionnaire about typical symptoms, signs and complications preceding the diagnosis. RESULTS: Abnormal thirst, frequent urination, weight loss, genital itching, stomatitis, visual disturbances, fatigue, confusion and (in men) balanitis were associated with glycaemic level irrespective of age, sex, BMI, BP, complications and antihypertensive treatment. Eighty-nine percent of the patients presented with one or more of these hyperglycaemic symptoms and signs, and the pre-diagnostic duration was typically less than 3 months. Only a few symptoms, signs and complications were associated with weight and BP. CONCLUSIONS/INTERPRETATION: In patients newly diagnosed with type 2 diabetes in family practice, typical diabetic symptoms, signs and complications are common. Typical diabetic symptoms and signs are associated with hyperglycaemia. The pre-diagnostic duration of hyperglycaemic symptoms and signs were typically short, thus questioning the feasibility of early detection relying on increased anticipatory care by GPs. In contrast, elevated levels of cardiovascular risk factors and longer pre-diagnostic duration of cardiovascular complications suggest these might have a central role in an early diagnosis of type 2 diabetes.

Diabetic retinopathy in newly diagnosed middle-aged and elderly diabetic patients. Prevalence and interrelationship with microalbuminuria and triglycerides.

BACKGROUND: The exact role of factors such as serum lipids, body mass index and (micro-)albuminuria as possible determinants of diabetic retinopathy remains to be determined. We have scrutinized the prevalence of diabetic retinopathy and its concomitants in terms of risk factors and other diabetic complications in newly diagnosed diabetic patients. METHODS: A population-based sample of 1,251 newly diagnosed diabetic patients aged 40 years or over was established in general practice. Median age was 65.3 years. Funduscopy was performed by practising ophthalmologists. Blood and urine analyses were centralised. RESULTS: The overall prevalence of diabetic retinopathy was 5.0%. Only three patients had proliferative diabetic retinopathy. As expected, diabetic retinopathy and renal involvement, as expressed by the urinary albumin/creatinine ratio. were strongly positively associated. An intriguing finding was that of an inverse relationship between fasting triglycerides and diabetic retinopathy, an association that proved to be confined to microalbuminuric patients. An inverse association between body mass index and diabetic retinopathy was found only univariately. CONCLUSION: The low prevalence of diabetic retinopathy cannot be explained by the screening method alone, but rather by early detection of diabetes in a non-selective patient sample. It seems that renal involvement modifies the expected relationship between diabetic retinopathy and triglycerides, but a pathophysiological mechanism is not available.

Optimization of preanalytical conditions and analysis of plasma glucose. 1. Impact of the new WHO and ADA recommendations on diagnosis of diabetes mellitus.

The new diagnostic criteria for type 2 diabetes from the American Diabetes Association (ADA) and World Health Organization (WHO) recommend measurements on plasma and a lowering of the glucose threshold for diabetes by 0.8 mmol/L. This narrows the distance between the upper end of the reference limit and the discriminatory level to a degree where analytical quality becomes critical. The quality demands for the preanalytical and analytical phase and their consequences on diagnostic performance have to be established in the new technical system, measuring in plasma rather than in capillary whole blood. Because of the instability of glucose in blood samples it is necessary to clarify the influence of different preanalytical and analytical factors on the number of false-positive and false-negative classifications. Thus the aim of the present study was to find optimal conditions for sampling, additives, storage, transport and analysis of plasma glucose combining feasibility with an analytical bias close to zero and a within-imprecision around 1%. We have documented the analytical performance of the method itself and its traceability to an international standard. The preanalytical conditions, such as influence of antiglycolytic agent NaF, conditions for plasma separation, storage temperature and storage time before and after plasma separation were investigated. In conclusion, we recommend that blood should be drawn in tubes containing heparin and NaF and kept on ice water for not more than 1 h until centrifugation at minimum 1000 x g for 10 min. The plasma is then stable for at least 48 h at room temperature.

Plasma glucose reference interval in a low-risk population. 2. Impact of the new WHO and ADA recommendations on the diagnosis of diabetes mellitus.

The aim of the study was to establish a reference interval of fasting venous plasma glucose (FPG) from healthy individuals. A prospective modified cross-sectional population-based study was made with random selection of 2100 persons in age-stratified groups > or = 18 years identified from the local Personal Identification Register. The invitation was accepted by 755 persons, of which 726 aged 18-92 years were eligible. They did not have a diabetes diagnosis, were non-pregnant and capable of fasting for 8 h. All participants filled in a questionnaire on medical risk factors. Blood for the FPG and haemoglobin Alc (HbAlc) measurements was drawn in accordance with a standardized procedure. A total of 302 participants carried diabetes risk indicators and were ruled out. The FPG concentrations in the remaining low-risk population (n=424) was ln Gaussian distributed. The FPG 97.50 centile in this group was 6.4 mmol/L (95% CI: 6.3-6.5 mmol/L), in contrast to the WHO and ADA theoretical limit of 6.1 mmol/L. Their diagnostic decision limit of 7.0 mmol/L FPG corresponded to the 99.86 centile of the FPG reference distribution (95% CI: 6.8-7.1). Subclassification of the reference population showed increasing FPG with increasing BMI and age and was higher in men than in women. The study determined the FPG 95% interfractile reference interval in a healthy population. The interval in glucose concentration between the 97.5 centile of the reference interval and the ADA-WHO diagnostic limit is very narrow. The clinical application of the diagnostic discriminator and the interpretation of the WHO-ADA grey zone from 6.1 to 7.0 mmol/L FPG may consequently be biased because of poorly defined limits and influence from BMI, age and gender.

Evaluation of systematic and random factors in measurements of fasting plasma glucose as the basis for analytical quality specifications in the diagnosis of diabetes. 3. Impact of the new WHO and ADA recommendations on diagnosis of diabetes mellitus.

On behalf of the Danish Society of Clinical Endocrinology and the Danish Society of Clinical Chemistry we were commissioned to evaluate the influence of analytical and pre-analytical systematic and random factors on the diagnosis of diabetes, in order to provide a tool for conclusions on the analytical quality specifications needed to diagnose diabetes. A systems analysis was performed in accordance with the principles for evaluation of analytical quality specifications. The clinical setting was defined--diagnosis of diabetes in accordance with the WHO and ADA criteria with determination of fasting plasma glucose concentration (FPG) > or =7.0 mmol/L in two independent samples--with well-documented data on In (loge)-Gaussian distribution of reference values from a low-risk population and values for within-subject biological variation taken from the literature. An investigation was made of the consequences for the clinical setting of assumed errors related to the measurement of FPG. Four approaches were investigated for a single sampling and measurement and also for two independent samples: one showing the percentage of healthy individuals who had values > or = 7.0 mmol/L, one illustrating the origin of biological set-points for results > or = 7.0 mmol/L, one showing the risk of being measured > or =7.0 mmol/L when the biological set-point is known, and one showing the combined bias and imprecision for assumed percentages of false-positive (FP), defined as measurements > or = 7.0 mmol/L for the low-risk population and false-negative (FN), defined as measurements <6.4 mmol/L (the upper reference limit) for diabetics. This leaves a "grey zone" which includes the upper part of low-risk individuals, and defined by ADA and WHO as "impaired fasting glucose" (IFG). In the analysis, increasing systematic and random errors (combined analytical and pre-analytical) were assumed, and for each error condition the fractions of FP and FN were calculated. This gave plots from which the combined allowable systematic and random errors could be read off for pre-determined clinically acceptable fractions of FP and FN. The analysis does not distinguish between pre-analytical and analytical errors, as specified information on one of these is needed for specification of the other. The investigation provides a reliable basis for estimation of the needed analytical quality, and thereby for decisions about analytical quality specifications for analysis of FPG in relation to diagnosis of diabetes under optimized pre-analytical and analytical conditions. Consequences of deviations from these ideal conditions are illustrated in the figures, and should be considered for the different approaches with different performance conditions.