Cardiovascular risk factors and incident albuminuria in screen-detected type 2 diabetes.

BACKGROUND: It is unclear whether cardiovascular risk factor modification influences the development of renal disease in people with type 2 diabetes identified through screening. We determined predictors of albuminuria 5 years after a diagnosis of screen-detected diabetes within the ADDITION-Europe study, a pragmatic cardiovascular outcome trial of multifactorial cardiovascular risk management. METHODS: In 1826 participants with newly diagnosed, screen-detected diabetes without albuminuria, we explored associations between risk of new albuminuria (≥2.5 mg mmol-1 for males and ≥3.5 mg mmol-1 for females) and (1) baseline cardio-metabolic risk factors and (2) changes from baseline to 1 year in systolic blood pressure (ΔSBP) and glycated haemoglobin (ΔHbA1c ) using logistic regression. RESULTS: Albuminuria developed in 268 (15%) participants; baseline body mass index and active smoking were independently associated with new onset albuminuria in 5 years after detection of diabetes. In a model adjusted for age, gender, baseline HbA1c and blood pressure, a 1% decrease in HbA1c and 5-mm Hg decrease in SBP during the first year were independently associated with lower risks of albuminuria (odds ratio), 95% confidence interval: 0.76, 0.62 to 0.91 and 0.94, 0.88 to 1.01, respectively. Further adjustment did not materially change these estimates. There was no interaction between ΔSBP and ΔHbA1c in relation to albuminuria risk, suggesting likely additive effects on renal microvascular disease. CONCLUSIONS: Baseline measurements and changes in HbA1c and SBP a year after diagnosis of diabetes through screening independently associate with new onset albuminuria 4 years later. Established multifactorial treatment for diabetes applies to cases identified through screening.

Cost-effectiveness of intensive multifactorial treatment compared with routine care for individuals with screen-detected Type 2 diabetes: analysis of the ADDITION-UK cluster-randomized controlled trial.

AIMS: To examine the short- and long-term cost-effectiveness of intensive multifactorial treatment compared with routine care among people with screen-detected Type 2 diabetes. METHODS: Cost-utility analysis in ADDITION-UK, a cluster-randomized controlled trial of early intensive treatment in people with screen-detected diabetes in 69 UK general practices. Unit treatment costs and utility decrement data were taken from published literature. Accumulated costs and quality-adjusted life years (QALYs) were calculated using ADDITION-UK data from 1 to 5 years (short-term analysis, n = 1024); trial data were extrapolated to 30 years using the UKPDS outcomes model (version 1.3) (long-term analysis; n = 999). All costs were transformed to the UK 2009/10 price level. RESULTS: Adjusted incremental costs to the NHS were £285, £935, £1190 and £1745 over a 1-, 5-, 10- and 30-year time horizon, respectively (discounted at 3.5%). Adjusted incremental QALYs were 0.0000, - 0.0040, 0.0140 and 0.0465 over the same time horizons. Point estimate incremental cost-effectiveness ratios (ICERs) suggested that the intervention was not cost-effective although the ratio improved over time: the ICER over 10 years was £82,250, falling to £37,500 over 30 years. The ICER fell below £30 000 only when the intervention cost was below £631 per patient: we estimated the cost at £981. CONCLUSION: Given conventional thresholds of cost-effectiveness, the intensive treatment delivered in ADDITION was not cost-effective compared with routine care for individuals with screen-detected diabetes in the UK. The intervention may be cost-effective if it can be delivered at reduced cost.

Variation in prescribing of lipid-lowering medication in primary care is associated with incidence of cardiovascular disease and all-cause mortality in people with screen-detected diabetes: findings from the ADDITION-Denmark trial.

AIMS: To examine variation between general practices in the prescription of lipid-lowering treatment to people with screen-detected Type 2 diabetes, and associations with practice and participant characteristics and risk of cardiovascular events and all-cause mortality. METHODS: Observational cohort analysis of data from 1533 people with screen-detected Type 2 diabetes aged 40-69 years from the ADDITION-Denmark study. One hundred and seventy-four general practices were cluster randomized to receive: (1) routine diabetes care according to national guidelines (623 individuals), or (2) intensive multifactorial target-driven management (910 individuals). Multivariable logistic regression was used to quantify the association between the proportion of individuals in each practice who redeemed prescriptions for lipid-lowering medication in the two years following diabetes diagnosis and a composite cardiovascular disease (CVD) outcome, adjusting for age, sex, prevalent chronic disease, baseline CVD risk factors, smoking and lipid-lowering medication, and follow-up time. RESULTS: The proportion of individuals treated with lipid-lowering medication varied widely between practices (0-100%). There were 118 CVD events over 9431 person-years of follow-up. For the whole trial cohort, the risk of CVD was significantly higher in practices in the lowest compared with the highest quartile for prescribing lipid-lowering medication [adjusted odds ratio (OR) 3.4, 95% confidence interval (CI) 1.6-7.3]. Similar trends were found for all-cause mortality. CONCLUSIONS: More frequent prescription of lipid-lowering treatment was associated with a lower incidence of CVD and all-cause mortality. Improved understanding of factors underlying practice variation in prescribing may enable more frequent use of lipid-lowering treatment. The results highlight the benefits of intensive treatment of people with screen-detected diabetes (Clinical Trials Registry No; NCT 00237549).

Does early intensive multifactorial therapy reduce modelled cardiovascular risk in individuals with screen-detected diabetes? Results from the ADDITION-Europe cluster randomized trial.

AIMS: Little is known about the long-term effects of intensive multifactorial treatment early in the diabetes disease trajectory. In the absence of long-term data on hard outcomes, we described change in 10-year modelled cardiovascular risk in the 5 years following diagnosis, and quantified the impact of intensive treatment on 10-year modelled cardiovascular risk at 5 years. METHODS: In a pragmatic, cluster-randomized, parallel-group trial in Denmark, the Netherlands and the UK, 3057 people with screen-detected Type 2 diabetes were randomized by general practice to receive (1) routine care of diabetes according to national guidelines (1379 patients) or (2) intensive multifactorial target-driven management (1678 patients). Ten-year modelled cardiovascular disease risk was calculated at baseline and 5 years using the UK Prospective Diabetes Study Risk Engine (version 3ß). RESULTS: Among 2101 individuals with complete data at follow up (73.4%), 10-year modelled cardiovascular disease risk was 27.3% (sd 13.9) at baseline and 21.3% (sd 13.8) at 5-year follow-up (intensive treatment group difference -6.9, sd 9.0; routine care group difference -5.0, sd 12.2). Modelled 10-year cardiovascular disease risk was lower in the intensive treatment group compared with the routine care group at 5 years, after adjustment for baseline cardiovascular disease risk and clustering (-2.0; 95% CI -3.1 to -0.9). CONCLUSIONS: Despite increasing age and diabetes duration, there was a decline in modelled cardiovascular disease risk in the 5 years following diagnosis. Compared with routine care, 10-year modelled cardiovascular disease risk was lower in the intensive treatment group at 5 years. Our results suggest that patients benefit from intensive treatment early in the diabetes disease trajectory, where the rate of cardiovascular disease risk progression may be slowed.

Insulin resistance and beta-cell function in different ethnic groups in Kenya: the role of abdominal fat distribution.

Little is known about the pathophysiology of diabetes in Africans. Thus, we assessed whether insulin resistance and beta-cell function differed by ethnicity in Kenya and whether differences were modified by abdominal fat distribution. A cross-sectional study in 1,087 rural Luo (n = 361), Kamba (n = 378), and Maasai (n = 348) was conducted. All participants had a standard 75-g oral glucose tolerance test (OGTT). Venous blood samples were collected at 0, 30, and 120 min. Serum insulin was analysed at 0 and 30 min. From the OGTT, we assessed the homoeostasis model assessment of insulin resistance by computer model, early phase insulin secretion, and disposition index (DI) dividing insulin secretion by insulin resistance. Abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) thickness were carried out by ultrasonography. Linear regression analyses were done to assess ethnic differences in insulin indices. The Maasai had 32 and 17% higher insulin resistance than the Luo and Kamba, respectively (p < 0.001). Early phase insulin secretion was 16% higher in the Maasai compared to the Luo (p < 0.001). DI was 12% (p = 0.002) and 10% (p = 0.015) lower in the Maasai compared to the Luo and Kamba, respectively. Adjustments of SAT (range 0.1-7.1 cm) and VAT (range 1.5-14.2 cm) largely explained these inter-group differences with the Maasai having the highest combined abdominal fat accumulation. The Maasai had the highest insulin resistance and secretion, but the lowest relative beta-cell function compared to the Luo and Kamba. These differences were primarily explained by abdominal fat distribution.

The pro-inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is associated with incident type 2 diabetes among overweight but not obese individuals with impaired glucose regulation: effect modification by smoking and body weight status.

AIMS/HYPOTHESIS: Recent evidence links the soluble urokinase plasminogen activator receptor (suPAR), a stable biomarker of systemic immune activation, to several chronic diseases, including type 2 diabetes. suPAR is also associated with adiposity and smoking. We hypothesised that this biomarker would be linked to incident type 2 diabetes in individuals with impaired glucose regulation and that this association would be modified by smoking and body weight status. METHODS: The study included 1,933 participants with impaired glucose regulation, who were drawn from the Danish arm of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION) and for whom data on suPAR, BMI and smoking were available. Logistic regression analysis was used to estimate the odds for incident type 2 diabetes per twofold increase in suPAR levels. Interactions between both smoking and body weight status and suPAR were tested. RESULTS: During a 3-year follow-up (599 incident diabetes cases), there was a 48% overall increase in the odds of developing type 2 diabetes per twofold increase in suPAR (p = 0.006). This association was modified by body weight status in overweight, but not in obese individuals (OR 2.36, 95% CI 1.48, 3.76 in overweight group), and by smoking status (OR 2.05, 95% CI 1.20, 3.51 in non-smokers). After adjustment for other diabetes risk factors, the association between suPAR and type 2 diabetes was attenuated in the whole sample and among non-smokers, but remained robust among overweight participants. CONCLUSIONS/INTERPRETATION: suPAR may be a good novel biomarker for systemic sub-clinical inflammation and immune activation linked to incident type 2 diabetes risk in overweight individuals and non-smokers. The observed interactions with adiposity and smoking should be investigated further.

Impact of early detection and treatment of diabetes on the 6-year prevalence of cardiac autonomic neuropathy in people with screen-detected diabetes: ADDITION-Denmark, a cluster-randomised study.

AIMS/HYPOTHESIS: There is limited evidence on how multifactorial treatment improves outcomes of diabetes when initiated in the lead time between detection by screening and diagnosis in routine clinical practice. Cardiac autonomic neuropathy (CAN) in people with diabetes indicates widespread damage to the autonomic nervous system, which may severely affect health and quality of life. We examined effects of early detection and subsequent intensive treatment of type 2 diabetes in primary care on the prevalence of CAN at the 6-year follow-up examination in a pragmatic cluster-randomised parallel group trial. METHODS: One hundred and ninety general practices were randomised to deliver either intensive multifactorial treatment (IT) or routine care (RC) as recommended by national guidelines to patients with type 2 diabetes, identified through a stepwise screening programme in the primary care setting. 1533 people (IT, n = 910; RC, n = 623) were identified and included. At the 6-year follow-up examination, measures of CAN were applied in an unselected subsample of 777 participants using heart rate variability analysis and standard tests of CAN. RESULTS: At the 6-year follow-up examination, the prevalence of early CAN was 15.1% in the RC group and 15.5% in the IT group, while manifest CAN was present in 7.1% and 7.3%, respectively. We found no statistically significant effect of intensive treatment on the prevalence of CAN compared with routine care. CONCLUSIONS/INTERPRETATION: In the Danish arm of the ADDITION Study, signs of CAN were highly prevalent 6 years after a screening-based diagnosis of type 2 diabetes. Intensive multifactorial treatment did not significantly affect the prevalence of CAN compared with routine care. However, at follow-up the level of medication was also high in the RC group.

Cardiorespiratory fitness and physical activity in Luo, Kamba, and Maasai of rural Kenya.

BACKGROUND: Although habitual physical activity energy expenditure (PAEE) and cardio-respiratory fitness (CRF) are now well-established determinants of metabolic disease, there is scarcity of such data from Africa. The aim of this study was to describe objectively measured PAEE and CRF in different ethnic populations of rural Kenya. METHODS: A cross-sectional study was done among 1,099 rural Luo, Kamba, and Maasai of Kenya. Participants were 17-68 years old and 60.9% were women. Individual heart rate (HR) response to a submaximal steptest was used to assess CRF (estimated VO(2) max). Habitual PAEE was measured with combined accelerometry and HR monitoring, with individual calibration of HR using information from the step test. RESULTS: Men had higher PAEE than women (∼78 vs. ∼67 kJ day(-1) kg(-1) , respectively). CRF was similar in all three populations (∼38 and ∼43 mlO(2) ·kg(-1) min(-1) in women and men, respectively), while habitual PAEE measures were generally highest in the Maasai and Kamba. About 59% of time was spent sedentary (<1.5 METs), with Maasai women spending significantly less (55%). Both CRF and PAEE were lower in older compared to younger rural Kenyans, a difference which was most pronounced for PAEE in Maasai (-6.0 and -11.9 kJ day(-1) kg(-1) per 10-year age difference in women and men, respectively) and for CRF in Maasai men (-4.4 mlO(2) ·min(-1) kg(-1) per 10 years). Adjustment for hemoglobin did not materially change these associations. CONCLUSION: Physical activity levels among rural Kenyan adults are high, with highest levels observed in the Maasai and Kamba. The Kamba may be most resilient to age-related declines in physical activity.

Does early intensive multifactorial treatment reduce total cardiovascular burden in individuals with screen-detected diabetes? Findings from the ADDITION-Europe cluster-randomized trial.

AIMS: To describe the total cardiovascular burden (cardiovascular morbidity or mortality, revascularization or non-traumatic amputation) in individuals with screen-detected diabetes in the ADDITION-Europe trial and to quantify the impact of the intervention on multiple cardiovascular events over 5 years. METHODS: In a pragmatic, cluster-randomized, parallel-group trial in four centres (Denmark; Cambridge, UK; the Netherlands; and Leicester, UK), 343 general practices were randomized to screening plus routine care (n = 1379 patients), or screening and promotion of target-driven, intensive treatment of multiple risk factors (n = 1678). We estimated the effect of the intervention on multiple cardiovascular events after diagnosis of diabetes using the Wei, Lin and Weissfeld method. RESULTS: Over 5.3 years, 167 individuals had exactly one cardiovascular event, 53 exactly two events, and 18 three or more events. The incidence rates (95% CI) of first events and any event per 1000 person-years were 14.6 (12.8-16.6) and 20.4 (18.2-22.6), respectively. There were non-significant reductions in the risk of a first (hazard ratio 0.83, 95% CI 0.65-1.05) and second primary endpoint (hazard ratio 0.70, 95% CI 0.43-1.12). The overall average hazard ratio for any event was 0.77 (95% CI 0.58-1.02). CONCLUSIONS: Early intensive multifactorial treatment was not associated with a significant reduction in total cardiovascular burden at 5 years. Focusing on first events in cardiovascular disease prevention trials underestimates the total cardiovascular burden to patients and the health service.

Diabetes in Greenland and its relationship with urbanization.

BACKGROUND AND AIM: Most studies show that diabetes increases with migration and urbanization. Previous studies from Greenland have shown inconsistent associations between cardiovascular risk and urbanization. Thus, the aim was to study the association between diabetes and urbanization among Greenland Inuit. METHODS: A total of 3089 adult Inuit aged 18 years and older participated in a geographically representative, population-based study 'Inuit Health in Transition Study'. The examination included a 75 g oral glucose tolerance test and anthropometric measurements. Information on socio-demographic characteristic and health behaviour was obtained by interview or questionnaire. The participants were categorized according to degree of urbanization into three groups based on current place of residence: (1) participants living in towns (> 2000 inhabitants), (2) participants living in small towns (< 2000 inhabitants) and (3) participants living in villages (< 500 inhabitants). RESULTS: The total prevalence of diabetes was 9% of which 79% were previously unknown. Nine per cent had impaired glucose tolerance and 19% had impaired fasting glycaemia (IFG). Compared with towns, odds rations (ORs) for diabetes and impaired fasting glycaemia were higher in small towns [OR(diabetes) = 1.5 (1.0-2.3), OR(IFG) = 1.9 (1.2-2.3)] and villages [OR(diabetes) = 1.2 (0.8-1.9), OR(IFG) = 1.3 (0.9-2.0)], whereas no association was seen for impaired glucose tolerance. The inverse association between urbanization and diabetes and impaired fasting glycaemia persisted after adjustment for relevant confounders. CONCLUSION: Diabetes and impaired fasting glycaemia decreased with urbanization contrary to the results of most studies. It appears that Greenland Inuit follow the pattern usually observed in industrialized countries with the highest risk of diabetes in the lower socio-economic groups.

The immune marker soluble urokinase plasminogen activator receptor is associated with new-onset diabetes in non-smoking women and men.

AIM: To explore the putative association of new-onset diabetes and the soluble urokinase plasminogen activator receptor (suPAR), which is a new and stable plasma marker of immune function and low-grade inflammation. This association has been previously suggested by using the less sensitive International Classification of Disease system to detect incident diabetes in the Danish MONICA 10 cohort. METHODS: The Danish National Diabetes Register enabled more accurate identification of incident diabetes during a median follow-up of 13.8 years in the Danish MONICA 10 cohort (n = 2353 generally healthy individuals). The soluble urokinase plasminogen activator receptor was measured by the ELISA method. To fulfil model assumptions, outcome analyses were stratified by age, and further by smoking, owing to the interaction between the soluble urokinase plasminogen activator receptor and smoking on new-onset diabetes (P < 0.0001). RESULTS: New-onset diabetes (n = 182) was associated with increased soluble urokinase plasminogen activator receptor levels (P = 0.013). Among 699 middle-aged (41 and 51 years) and 564 older (61 and 71 years) non-smokers, participants in the upper soluble urokinase plasminogen activator receptor quartile had a sex- and age-adjusted relative risk of 6.01 (95% CI 2.17-16.6, P < 0.0006) and relative risk of 3.25 (95% CI 1.51-6.98, P = 0.0025), respectively, for new-onset diabetes compared with participants in the lowest quartile. This relationship remained significant after additional adjustments for C-reactive protein and leukocytes or fasting glucose and insulin or BMI (P < 0.05). The soluble urokinase plasminogen activator receptor was not related to incident diabetes among smokers (P ≥ 0.85). CONCLUSIONS: In these explorative analyses, the soluble urokinase plasminogen activator receptor associated independently with incident diabetes in non-smokers, supporting an immune origin of Type 2 diabetes. Competing disease risk may explain lack of association among smokers.

The effects of adding group-based lifestyle counselling to individual counselling on changes in plasma glucose levels in a randomized controlled trial: the Inter99 study.

AIM: This study aimed to assess whether group-based lifestyle counselling offered to a high-risk population subgroup had any effect beyond individual multifactorial interventions on fasting plasma glucose (FPG) and 2-h plasma glucose (2hPG) changes. METHODS: In a population-based study of 6784 participants, 4053 were determined to be at high risk based on a risk estimate of ischaemic heart disease or the presence of risk factors (smoking, hypertension, hypercholesterolaemia, obesity, impaired glucose tolerance). Of these subjects, 90% were randomized to high-intensity intervention (group A) and 10% to low-intensity intervention (group B). All participants went through health examinations, risk assessments and individual lifestyle counselling. Participants in group A were further offered group-based lifestyle counselling. The intervention was repeated after 1 and 3 years. A total of 2738 participants free of diabetes at baseline (1999-2001) and with at least one FPG and/or 2hPG measurement during 5 years of follow-up were included in the analyses. Differences in changes of plasma glucose between groups A and B were analyzed using multilevel linear regression. RESULTS: For FPG, crude 5-year changes were significantly different between the two groups (group A: -0.003 mmol/L vs group B: -0.079 mmol/L; P=0.0427). After adjusting for relevant confounders, no differences in FPG changes were observed (P=0.116). Also, no significant differences in the 5-year changes in 2hPG between the two groups were observed (group A: - 0.127 mmol/L vs group B: -0.201 mmol/L; P=0.546). CONCLUSION: Offering additional group-based intervention to a high-risk population subgroup had no clinical effects on changes in plasma glucose beyond those of individualized multifactorial interventions.

Comparing incident diabetes as defined by fasting plasma glucose or by HbA(1c). The AusDiab, Inter99 and DESIR studies.

AIM: We examined the ability of fasting plasma glucose and HbA(1c) to predict 5-year incident diabetes for an Australian cohort and a Danish cohort and 6-year incident diabetes for a French cohort, as defined by the corresponding criteria. METHODS: We studied 6025 men and women from AusDiab (Australian), 4703 from Inter99 (Danish) and 3784 from DESIR (French), not treated for diabetes and with fasting plasma glucose < 7.0 mmol/l and HbA(1c) < 48 mmol/mol (6.5%) at inclusion. Diabetes was defined as fasting plasma glucose ≥ 7.0 mmol/l and/or treatment for diabetes or as HbA(1c) ≥ 48 mmol/mol (6.5%) and/or treatment for diabetes. RESULTS: For AusDiab, incident fasting plasma glucose-defined diabetes was more frequent than HbA(1c) -defined diabetes (P(McNemar)<0.0001), the reverse applied to Inter99 (P(McNemar) < 0.007) and for DESIR there was no difference (P(McNema)=0.17). Less than one third of the incident cases were detected by both criteria. Logistic regression models showed that baseline fasting plasma glucose and baseline HbA(1c) predicted incident diabetes defined by the corresponding criteria. The standardized odds ratios (95% confidence interval) for HbA(1c) were a little higher than for fasting plasma glucose, but not significantly so. They were respectively, 5.0 (4.1-6.1) and 4.1 (3.5-4.9) for AusDiab, 5.0 (3.6-6.8) and 4.8 (3.6-6.3) for Inter99, 4.8 (3.6-6.5) and 4.6 (3.6-5.9) for DESIR. CONCLUSIONS: Fasting plasma glucose and HbA(1c) are good predictors of incident diabetes defined by the corresponding criteria. Despite Diabetes Control and Complications Trial-alignment of the three HbA(1c) assays, there was a large difference in the HbA(1c) distributions between these studies, conducted some 10 years ago. Thus, it is difficult to compare absolute values of diabetes prevalence and incidence based on HbA(1c) measurements from that time.

Screening for type 2 diabetes. Lessons from the ADDITION-Europe study.

AIMS: To describe and compare attendance rates and the proportions of people identified with Type 2 diabetes mellitus in people with previously unknown diabetes who participated in screening programmes undertaken in general practice in the UK, Denmark and the Netherlands as part of the ADDITION-Europe study. METHODS: In Cambridge, routine computer data searches were conducted to identify individuals aged 40-69 years at high risk of Type 2 diabetes using the Cambridge Diabetes Risk Score. In Denmark, the Danish Diabetes Risk Score was mailed to individuals aged 40-69 years, or completed by patients visiting their general practitice. In the Netherlands, the Hoorn Symptom Risk Questionnaire was mailed to individuals aged 50-69 years. In these three centres, high-risk individuals were invited to attend subsequent steps in the screening programme, including random blood glucose, HbA(1c) , fasting blood glucose and/or oral glucose tolerance test. In Leicester, eligible people aged 40-69 years were invited directly for an oral glucose tolerance test. In all centres, Type 2 diabetes was defined according to World Health Organization 1999 diagnostic criteria. RESULTS: Attendance rates ranged from 20.2% (oral glucose tolerance test in Leicester without pre-stratification) to 95.1% (random blood glucose in opportunistic screening in Denmark in high-risk people). The percentage of people with newly detected Type 2 diabetes from the target population ranged from 0.33% (Leicester) to 1.09% (the Netherlands). CONCLUSIONS: Screening for Type 2 diabetes was acceptable and feasible, but relatively few participants were diagnosed in all participating centres. Different strategies may be required to increase initial attendance and ensure completion of screening programmes.

HbA1c and cardiovascular risk score identify people who may benefit from preventive interventions: a 7 year follow-up of a high-risk screening programme for diabetes in primary care (ADDITION), Denmark.

AIMS/HYPOTHESIS: The measurement of HbA(1c) is suggested as a diagnostic test for diabetes. Screening for diabetes also identifies individuals with elevated cardiovascular risk but who are free of diabetes. This study aims to assess whether screening by HbA(1c) or glucose measures alone, or in combination with a cardiovascular risk assessment, identifies people who may benefit from preventive interventions, i.e. people with screen detected diabetes and people belonging to groups with excess mortality, during a median follow-up of 7 years. METHODS: A population-based, stepwise high-risk screening programme was performed in 193 family practices from 2001 to 2006. Individuals aged between 40 and 69 years (N = 163,185) were sent a diabetes risk questionnaire. Of these, 20,916 people at risk of diabetes were stratified by glucose measures (normal glucose tolerance [NGT], impaired fasting glucose [IFG], impaired glucose tolerance [IGT] and diabetes), HbA(1c) (<6%; 6.0-6.4%; or ≥ 6.5%) and cardiovascular risk (heart SCORE <5 or ≥ 5). People were followed for a median of 7 years or until death. Excess mortality was calculated using the Cox hazard ratio (HR). RESULTS: SCORE ≥ 5 identified 91.7% (95% CI 91.1-92.3%) of those who might benefit from preventive interventions. SCORE ≥ 5 in combination with HbA(1c) ≥ 6.0% identified 96.7% (95% CI 96.3-97.0%), compared with 97.6% (95%CI 97.2-97.9%) in combination with glucose measures. Glucose measures or HbA(1c) alone identified 26.1% (95% CI 25.2-27.0%) and 19.8% (95% CI 19.0-20.6%), respectively. CONCLUSION/INTERPRETATION: In a population-based high risk screening programme in primary care, HbA(1c) ≥ 6.0% combined with an elevated cardiovascular risk assessment (SCORE ≥ 5) can feasibly be used to identify those who may benefit from preventive lifestyle intervention and/or polypharmacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00237549. FUNDING: The study received unrestricted grants from Novo Nordisk, Novo Nordisk Scandinavia, Astra Denmark, Pfizer Denmark, GlaxoSmithKline Pharma Denmark, Servier Denmark and HemoCue Denmark.

The Evaluation of Screening and Early Detection Strategies for Type 2 Diabetes and Impaired Glucose Tolerance (DETECT-2) update of the Finnish diabetes risk score for prediction of incident type 2 diabetes.

AIMS/HYPOTHESIS: The Finnish diabetes risk questionnaire is a widely used, simple tool for identification of those at risk for drug-treated type 2 diabetes. We updated the risk questionnaire by using clinically diagnosed and screen-detected type 2 diabetes instead of drug-treated diabetes as an endpoint and by considering additional predictors. METHODS: Data from 18,301 participants in studies of the Evaluation of Screening and Early Detection Strategies for Type 2 Diabetes and Impaired Glucose Tolerance (DETECT-2) project with baseline and follow-up information on oral glucose tolerance status were included. Incidence of type 2 diabetes within 5 years was used as the outcome variable. Improvement in discrimination and classification of the logistic regression model was assessed by the area under the receiver-operating characteristic (ROC) curve and by the net reclassification improvement. Internal validation was by bootstrapping techniques. RESULTS: Of the 18,301 participants, 844 developed type 2 diabetes in a period of 5 years (4.6%). The Finnish risk score had an area under the ROC curve of 0.742 (95% CI 0.726-0.758). Re-estimation of the regression coefficients improved the area under the ROC curve to 0.766 (95% CI 0.750-0.783). Additional items such as male sex, smoking and family history of diabetes (parent, sibling or both) improved the area under the ROC curve and net reclassification. Bootstrapping showed good internal validity. CONCLUSIONS/INTERPRETATION: The predictive value of the original Finnish risk questionnaire could be improved by adding information on sex, smoking and family history of diabetes. The DETECT-2 update of the Finnish diabetes risk questionnaire is an adequate and robust predictor for future screen-detected and clinically diagnosed type 2 diabetes in Europid populations.

HbA1(c) and mean blood glucose show stronger associations with cardiovascular disease risk factors than do postprandial glycaemia or glucose variability in persons with diabetes: the A1C-Derived Average Glucose (ADAG) study.

AIMS: Increased glucose excursions and postprandial hyperglycaemia have been suggested as unique risk factors for cardiovascular disease (CVD) and mortality in patients with diabetes mellitus. Much of the evidence is based on a single 2 h glucose value after oral glucose tolerance testing in epidemiological studies. We examined the association between various indices of glycaemia measured during everyday activities and metabolic CVD risk factors in the A1C-Derived Average Glucose (ADAG) study. METHODS: Participants (268 with type 1 diabetes, 159 with type 2 diabetes) completed 16 weeks of intensive continuous glucose monitoring (CGM) and self-monitoring of blood glucose (SMBG). From these data, common indices of postprandial glycaemia, overall hyperglycaemia, glucose variability and HbA1(c) were derived. The associations between glycaemic indices and known CVD risk factors (lipids, high-sensitivity C-reactive protein and blood pressure) were explored in linear regression models. RESULTS: For both diabetes types, the overall strongest associations with CVD risk factors were seen for the measures of average glycaemia (mean blood glucose and HbA1(c)). Associations between self-monitored postprandial and fasting glucose and CVD risk factors were weaker, but significant. Measurements of blood glucose variability showed non-significant associations. Overall, calculations based on CGM were not more informative than those based on frequent SMBG. CONCLUSIONS/INTERPRETATION: Mean glycaemia and HbA1(c) show consistent and stronger associations with CVD risk factors than fasting glucose or postprandial glucose levels or measures of glucose variability in patients with diabetes.

Cumulative glycaemia as measured by lens fluorometry: association with retinopathy in type 2 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to assess the association between lifelong cumulative glycaemia estimated by lens fluorometry and the presence of retinopathy in individuals with type 2 diabetes. METHODS: We carried out a cross-sectional population-based study of 970 participants aged between 30 and 60 years, of which 170 were diagnosed with diabetes on screening (WHO 1999 criteria) and 35 had known type 2 diabetes. Procedures included clinical and laboratory examinations, non-invasive assessment of the intrinsic fluorescence of the lens of the eye, and seven-field fundus photography. RESULTS: Retinopathy was found in 46 (22%) of 205 participants with type 2 diabetes. In a logistic regression analysis controlling for age, sex and diabetes status (screen-detected or known), a two-fold increase in lens fluorescence increased the odds for retinopathy by 3.46 (95% CI 1.25-9.55, p = 0.017). The association was marginally significant (OR 3.00 [95% CI 1.00-9.01], p = 0.050) when also adjusted for smoking, systolic blood pressure, body mass index and HbA(1c). CONCLUSIONS/INTERPRETATION: Diabetic retinopathy was related to cumulative lifelong glycaemia as estimated by lens fluorometry in participants with type 2 diabetes. This supports the hypothesis that retinopathy is a marker of lifelong elevated glycaemia as well as of the unknown, pre-diagnostic duration of type 2 diabetes. The powerful association between lens fluorescence and retinopathy underscores the importance of strict long-term glycaemic control in the prevention of retinopathy in people with diabetes.

HbA1c as predictor of all-cause mortality in individuals at high risk of diabetes with normal glucose tolerance, identified by screening: a follow-up study of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION), Denmark.

AIMS/HYPOTHESIS: Stepwise screening for type 2 diabetes will not only identify people with the disease or some other form of dysglycaemia (impaired fasting glucose or impaired glucose tolerance), but also many individuals who are phenotypically at high risk of developing diabetes, but currently have normal glucose tolerance (NGT). We therefore sought to assess whether HbA(1c) adds prognostic information in relation to all-cause mortality in people who have NGT and a high risk of type 2 diabetes mellitus. METHODS: In a Danish population-based stepwise screening programme for type 2 diabetes mellitus in general practice, we identified 15,634 persons at high risk of type 2 diabetes, who had NGT and a recorded HbA(1c) measurement. As comparison groups, we included 1,401 people identified as having type 2 diabetes mellitus and 8,149 individuals characterised as being at low risk of diabetes. All individuals were followed from time of screening (April 2001 to December 2006) until death or 31 October 2009. Excess mortality was estimated using Cox proportional hazard models with all-cause mortality as the outcome measure. RESULTS: Compared with individuals with NGT and HbA(1c) below 6.0%, adjusted hazard ratios were: 1.21 (95% CI 0.95-1.56) for individuals with NGT and HbA(1c) between 6.0% and 6.5%; 2.48 (95% CI 1.23-4.99) for individuals with NGT and HbA(1c) 6.5% or above (in this group there were eight deaths among 68 individuals); 1.73 (95% CI 1.40-2.13) for individuals with type 2 diabetes mellitus. CONCLUSIONS/INTERPRETATION: HbA(1c) level in people with NGT and at high risk of diabetes was clearly associated with increased all-cause mortality.