Pharmacodynamic mechanisms behind a refractory state in inflammatory bowel disease.

BACKGROUND AND AIMS: Biological therapy for inflammatory bowel disease is efficient in many cases but not all. The underlying molecular mechanisms behind non-response to biological therapy in inflammatory bowel disease are poorly described. Therefore, we aimed to characterize the mucosal cytokine transcript profile in non-immunogenic, non-responder patients with adequate trough level. MATERIAL AND METHODS: Patients with ulcerative colitis (UC) (n = 21) and Crohn's disease (CD) (n = 12) with non-response to biological therapy (anti-tumor necrosis factor (TNF) or vedolizumab) were included. Reference groups were A: untreated patients with UC or CD at debut of disease who had severe 1-year outcome, B: patients with UC or CD treated to endoscopic remission with biological agents, and C: healthy normal controls. Mucosal transcripts of TNF, interleukin (IL)17 and IL23 were measured by reverse transcription real-time quantitative polymerase chain reaction. Results Of the non-responders, 2 out of 12 CD and 1 out of 21 UC patients needed surgery during follow-up. Of the remaining non-responding patients, 8 out of 10 CD and 12 out of 20 UC patients switched biologic treatment. The remaining 2 CD and 8 UC patients continued treatment with the same biological agent with the addition of steroids, immunomodulators (AZA/MTX) and /or local steroids/5ASA. Twelve (8 UC/4 CD) out of 20 IBD patients were still non-responders after changing biological therapy to either anti-TNF (2), vedolizumab (9) or ustekinumab (1). The transcripts of IL17, IL23 and TNF were significantly upregulated in the non-response group compared to normal controls and patients in remission. In UC, 24% of the non-responders had normal mucosal TNF transcript indicating a non-TNF mediated inflammation. No obvious differences in gene expression were observed between primary and secondary non-responders, nor between anti-TNF and vedolizumab non-responders. CONCLUSIONS: Mucosal transcripts of IL17 and IL23 are highly associated with non-response to biological therapy, whereas some UC patients may also have a non-TNF mediated inflammatory pathway.

Discovery and validation of mucosal TNF expression combined with histological score - a biomarker for personalized treatment in ulcerative colitis.

BACKGROUND: There are no accurate markers that can predict clinical outcome in ulcerative colitis at time of diagnosis. The aim of this study was to explore a comprehensive data set to identify and validate predictors of clinical outcome in the first year following diagnosis. METHODS: Treatment naive-patients with ulcerative colitis were included at time of initial diagnosis from 2004 to 2014, followed by a validation study from 2014 to 2018. Patients were treated according to clinical guidelines following a standard step-up regime. Patients were categorized according to the treatment level necessary to achieve clinical remission: mild, moderate and severe. The biopsies were assessed by Robarts histopathology index (RHI) and TNF gene transcripts. RESULTS: We included 66 patients in the calibration cohort and 89 patients in the validation. Mucosal TNF transcripts showed high test reliability for predicting severe outcome in UC. When combined with histological activity (RHI) scores the test improved its diagnostic reliability. Based on the cut-off values of mucosal TNF and RHI scores from the calibration cohort, the combined test had still high reliability in the validation cohort (specificity 0.99, sensitivity 0.44, PPV 0.89, NPV 0.87) and a diagnostic odds-ratio (DOR) of 54. CONCLUSIONS: The combined test using TNF transcript and histological score at debut of UC can predict severe outcome and the need for anti-TNF therapy with a high level of precision. These validated data may be of great clinical utility and contribute to a personalized medical approach with the possibility of top-down treatment for selected patients.

Linking glycemic dysregulation in diabetes to symptoms, comorbidities, and genetics through EHR data mining.

Diabetes is a diverse and complex disease, with considerable variation in phenotypic manifestation and severity. This variation hampers the study of etiological differences and reduces the statistical power of analyses of associations to genetics, treatment outcomes, and complications. We address these issues through deep, fine-grained phenotypic stratification of a diabetes cohort. Text mining the electronic health records of 14,017 patients, we matched two controlled vocabularies (ICD-10 and a custom vocabulary developed at the clinical center Steno Diabetes Center Copenhagen) to clinical narratives spanning a 19 year period. The two matched vocabularies comprise over 20,000 medical terms describing symptoms, other diagnoses, and lifestyle factors. The cohort is genetically homogeneous (Caucasian diabetes patients from Denmark) so the resulting stratification is not driven by ethnic differences, but rather by inherently dissimilar progression patterns and lifestyle related risk factors. Using unsupervised Markov clustering, we defined 71 clusters of at least 50 individuals within the diabetes spectrum. The clusters display both distinct and shared longitudinal glycemic dysregulation patterns, temporal co-occurrences of comorbidities, and associations to single nucleotide polymorphisms in or near genes relevant for diabetes comorbidities.

Effect of population screening for type 2 diabetes and cardiovascular risk factors on mortality rate and cardiovascular events: a controlled trial among 1,912,392 Danish adults.

AIMS/HYPOTHESIS: Health check programmes for chronic disease have been introduced in a number of countries. However, there are few trials assessing the benefits and harms of these screening programmes at the population level. In a post hoc analysis, we evaluated the effect of population-based screening for type 2 diabetes and cardiovascular risk factors on mortality rates and cardiovascular events. METHODS: This register-based, non-randomised, controlled trial included men and women aged 40-69 years without known diabetes who were registered with a general practice in Denmark (n = 1,912,392). Between 2001 and 2006, 153,107 individuals registered with 181 practices participating in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION)-Denmark study were sent a diabetes risk score questionnaire. Individuals at moderate-to-high risk were invited to visit their GP for assessment of diabetes status and cardiovascular risk (screening group). The 1,759,285 individuals registered with all other general practices in Denmark constituted the retrospectively constructed no-screening (control) group. Outcomes were mortality rate and cardiovascular events (cardiovascular disease death, non-fatal ischaemic heart disease or stroke). The analysis was performed according to the intention-to-screen principle. RESULTS: Among the screening group, 27,177 (18%) individuals attended for assessment of diabetes status and cardiovascular risk. Of these, 1,533 were diagnosed with diabetes. During a median follow-up of 9.5 years, there were 11,826 deaths in the screening group and 141,719 in the no-screening group (HR 0.99 [95% CI 0.96, 1.02], p = 0.66). There were 17,941 cardiovascular events in the screening group and 208,476 in the no-screening group (HR 0.99 [0.96, 1.02], p = 0.49). CONCLUSIONS/INTERPRETATION: A population-based stepwise screening programme for type 2 diabetes and cardiovascular risk factors among all middle-aged adults in Denmark was not associated with a reduction in rate of mortality or cardiovascular events between 2001 and 2012.

Does training of general practitioners for intensive treatment of people with screen-detected diabetes have a spillover effect on mortality and cardiovascular morbidity in 'at risk' individuals with normoglycaemia? Results from the ADDITION-Denmark cluster-randomised controlled trial.

AIMS/HYPOTHESIS: Within a trial of intensive treatment of people with screen-detected diabetes, we aimed to assess a potential spillover effect of the trial intervention on incident cardiovascular disease (CVD) and all-cause mortality among people who screened positive on a diabetes risk questionnaire but who were normoglycaemic. METHODS: In the Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen-Detected Diabetes in Primary Care (ADDITION)-Denmark trial, 175 general practices were cluster-randomised into: (1) screening plus routine care of individuals with screen-detected diabetes (control group); or (2) screening plus training and support in intensive multifactorial treatment of individuals with screen-detected diabetes (intervention group). We identified all individuals who screened positive on a diabetes risk questionnaire in ADDITION-Denmark but were normoglycaemic following biochemical testing for use in this secondary analysis. After a median 8.9 years follow-up, we used data from national registers to compare rates of first CVD events and all-cause mortality in individuals in the routine care group with those in the intensive treatment group. RESULTS: In total, 21,513 individuals screened positive for high risk of diabetes but were normoglycaemic on biochemical testing in ADDITION-Denmark practices between 2001 and 2006 (10,289 in the routine care group and 11,224 in the intensive treatment group). During 9 years of follow-up, there were 3784 first CVD events and 1748 deaths. The incidence of CVD was lower among the intensive treatment group compared with the routine care group (HR 0.92 [95% CI 0.85, 0.99]). This association was stronger among individuals at highest CVD risk (heart SCORE ≥ 10; HR 0.85 [95% CI 0.75, 0.96]). There was no difference in mortality between the two treatment groups (HR 1.02 [95% CI 0.92, 1.14]). CONCLUSIONS/INTERPRETATION: Training of general practitioners to provide target-driven intensive management of blood glucose levels and other cardiovascular risk factors showed some evidence of a spillover effect on the risk of CVD over a 9 year period among individuals at high risk of diabetes. The effect was particularly pronounced among those at highest risk of CVD. There was no effect on mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT00237549.

Repeated intensified infliximab induction - results from an 11-year prospective study of ulcerative colitis using a novel treatment algorithm.

BACKGROUND: Anti-tumour necrosis factor (TNF) agents play a pivotal role in the treatment of moderate to severe ulcerative colitis (UC), and yet, no international consensus on when to discontinue therapy exists. OBJECTIVE: The aim of this study is to study the long-term performance of a treatment algorithm of repeated intensified induction therapy with infliximab (IFX) to remission, followed by discontinuation in patients with UC. PATIENTS AND METHODS: Patients with moderate to severe UC were enroled in an open prospective study design. The following algorithm was implemented: (a) intensified induction treatment to remission (Ulcerative Colitis Disease Activity Index score 0-2); (b) discontinuation of IFX; and (c) reinduction treatment if relapse. Mucosal gene expression for TNF was measured with qPCR. RESULTS: A total of 116 patients were included. The median observation time was 47 and 51 months in intention to treat and per protocol. Remission rates of the first three inductions were 95, 93 and 91% per protocol and 83, 56 and 59% by intention to treat. The median time in remission was 40 months per protocol and 34 months by intention to treat. Long-term remission without further anti-TNF treatment during the observation period was obtained for 41%, with a median observation time of 48 months (range: 18-129 months). The median time to relapse was 33 and 11 months with/without normalization of mucosal TNF, respectively. The 5-year success rate for maintaining the effect of IFX in the algorithm was 66%. CONCLUSION: The treatment algorithm is highly effective for achieving long-term clinical remission in UC. Normalization of mucosal TNF gene expression predicts long-term remission upon discontinuation of IFX.

Drug safety and the impact of drug warnings: An interrupted time series analysis of diabetes drug prescriptions in Germany and Denmark.

OBJECTIVE: To analyse the impact of drug safety warnings from the European Medicines Agency (EMA) on drug utilisation and their interaction with information released through national reimbursement bodies. METHODS: Insurance claims data on anti-diabetic drug prescriptions in primary care in Germany and Denmark were analysed using interrupted time series analysis, with EMA drug warnings for thiazolidinediones (TZDs) in 2007 and 2011 as the intervention. Monthly drug utilisation data per substance in defined daily dosages (DDD) consumed per 1000 insurees were retrieved from the Danish national drug prescriptions register and one large statutory sickness fund in Germany. RESULTS: TZDs were generally reimbursed in Germany but restricted to individual reimbursement in Denmark. Consequently, utilisation of TZDs was much higher in Germany in 2007 compared with Denmark. For rosiglitazone, the drug warning had a significant impact on utilisation, reducing the number of DDD per 1000 insurees per day by -0.0105 in Denmark and -0.0312 in Germany (p-values<0.05). For pioglitazone, neither of the drug warnings had a significant effect on utilisation. CONCLUSION: The impact of EMA drug warnings differed across countries and might be mediated by information released through national reimbursement bodies and physician associations. Increasing complexity of new drugs and modified approval procedures require a strengthening of information exchange between drug regulation bodies and physicians to ensure patient safety.

A randomised trial of the effect and cost-effectiveness of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with screen-detected type 2 diabetes: the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION-Europe) study.

BACKGROUND: Intensive treatment (IT) of cardiovascular risk factors can halve mortality among people with established type 2 diabetes but the effects of treatment earlier in the disease trajectory are uncertain. OBJECTIVE: To quantify the cost-effectiveness of intensive multifactorial treatment of screen-detected diabetes. DESIGN: Pragmatic, multicentre, cluster-randomised, parallel-group trial. SETTING: Three hundred and forty-three general practices in Denmark, the Netherlands, and Cambridge and Leicester, UK. PARTICIPANTS: Individuals aged 40-69 years with screen-detected diabetes. INTERVENTIONS: Screening plus routine care (RC) according to national guidelines or IT comprising screening and promotion of target-driven intensive management (medication and promotion of healthy lifestyles) of hyperglycaemia, blood pressure and cholesterol. MAIN OUTCOME MEASURES: The primary end point was a composite of first cardiovascular event (cardiovascular mortality/morbidity, revascularisation and non-traumatic amputation) during a mean [standard deviation (SD)] follow-up of 5.3 (1.6) years. Secondary end points were (1) all-cause mortality; (2) microvascular outcomes (kidney function, retinopathy and peripheral neuropathy); and (3) patient-reported outcomes (health status, well-being, quality of life, treatment satisfaction). Economic analyses estimated mean costs (UK 2009/10 prices) and quality-adjusted life-years from an NHS perspective. We extrapolated data to 30 years using the UK Prospective Diabetes Study outcomes model [version 1.3; (©) Isis Innovation Ltd 2010; see www.dtu.ox.ac.uk/outcomesmodel (accessed 27 January 2016)]. RESULTS: We included 3055 (RC, n = 1377; IT, n = 1678) of the 3057 recruited patients [mean (SD) age 60.3 (6.9) years] in intention-to-treat analyses. Prescription of glucose-lowering, antihypertensive and lipid-lowering medication increased in both groups, more so in the IT group than in the RC group. There were clinically important improvements in cardiovascular risk factors in both study groups. Modest but statistically significant differences between groups in reduction in glycated haemoglobin (HbA1c) levels, blood pressure and cholesterol favoured the IT group. The incidence of first cardiovascular event [IT 7.2%, 13.5 per 1000 person-years; RC 8.5%, 15.9 per 1000 person-years; hazard ratio 0.83, 95% confidence interval (CI) 0.65 to 1.05] and all-cause mortality (IT 6.2%, 11.6 per 1000 person-years; RC 6.7%, 12.5 per 1000 person-years; hazard ratio 0.91, 95% CI 0.69 to 1.21) did not differ between groups. At 5 years, albuminuria was present in 22.7% and 24.4% of participants in the IT and RC groups, respectively [odds ratio (OR) 0.87, 95% CI 0.72 to 1.07), retinopathy in 10.2% and 12.1%, respectively (OR 0.84, 95% CI 0.64 to 1.10), and neuropathy in 4.9% and 5.9% (OR 0.95, 95% CI 0.68 to 1.34), respectively. The estimated glomerular filtration rate increased between baseline and follow-up in both groups (IT 4.31 ml/minute; RC 6.44 ml/minute). Health status, well-being, diabetes-specific quality of life and treatment satisfaction did not differ between the groups. The intervention cost £981 per patient and was not cost-effective at costs ≥ £631 per patient. CONCLUSIONS: Compared with RC, IT was associated with modest increases in prescribed treatment, reduced levels of risk factors and non-significant reductions in cardiovascular events, microvascular complications and death over 5 years. IT did not adversely affect patient-reported outcomes. IT was not cost-effective but might be if delivered at a reduced cost. The lower than expected event rate, heterogeneity of intervention delivery between centres and improvements in general practice diabetes care limited the achievable differences in treatment between groups. Further follow-up to assess the legacy effects of early IT is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT00237549. FUNDING DETAILS: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 64. See the NIHR Journals Library website for further project information.

Incidence of register-based diabetes 10 years after a stepwise diabetes screening programme: the ADDITION-Denmark study.

AIMS/HYPOTHESIS: Screening programmes for type 2 diabetes inevitably find more people at high risk of developing diabetes than people with undiagnosed prevalent diabetes. We describe the incidence of diabetes for risk groups according to advancement in a screening process. METHODS: In 2001-2006, a diabetes screening programme based on the Danish diabetes risk score and measures of HbA1c and glucose was carried out in Danish general practices. The present study includes 13,249 individuals with low diabetes risk scores and 22,726 with high diabetes risk scores but no diabetes according to WHO 1999 criteria. Seven incremental levels of diabetes risk were defined and followed for incident diabetes recorded in the Danish National Diabetes Register until December 2012. For each group, cumulative diabetes incidence was calculated. Incidence rates and rate ratios were estimated by Poisson regression analyses. RESULTS: After 10 years of follow-up 1,164 new diabetes cases were registered. Incidence rates were 1.0, 4.2, 14.5, 28.8 and 52.6 per 1,000 person-years in individuals at low risk and in those with normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance and one diabetic glucose value, respectively. For each step in the screening algorithm, the risk of developing diabetes was higher than in the previous step. CONCLUSIONS/INTERPRETATION: The risk of developing clinical diabetes in people who screen negative for diabetes depends on the level of risk stratification at screening, even at lower risk levels. This risk increases markedly in the presence of impaired glucose regulation. These results can inform policy recommendations concerning prevention strategies following screening.

Normalization of mucosal tumor necrosis factor-α: A new criterion for discontinuing infliximab therapy in ulcerative colitis.

BACKGROUND: Biological agents such as anti-tumor necrosis factor (TNF) induce remission in ulcerative colitis. There is however no consensus regarding the discontinuation of this treatment. AIM: The aim of this study is to assess whether clinical parameters and mucosal cytokine mRNAs in healed colonic mucosa can predict long-term remission in ulcerative colitis following discontinuation of infliximab (IFX) therapy. METHODS: The prospective Tromsø Inflammatory Bowel Disease (IBD) Study is based on an intensified induction treatment algorithm with IFX to achieve disease remission. Following clinical and endoscopic remission, IFX treatment was discontinued, and follow-up until relapse was performed. Patients who achieved clinical and endoscopic remission following an induction course of IFX were included. Expression levels of TNF alpha (TNF), interferon gamma (IFNG), interleukin (IL) 6 (IL6), IL17A, IL23, and transforming growth factor beta (TGFB) were quantified by real-time PCR in mucosal biopsies obtained at colonoscopy. Remission was defined as Ulcerative Colitis Disease Activity Index (UCDAI) below 3, and an endoscopic sub-score of 0-1. Relapse was defined as UCDAI score >3 and endoscopic sub-score >1. Mucosal cytokine transcript levels from 20 non-IBD patients with a normal colonoscopy served as control group. RESULTS: Of the 45 patients included, twenty patients (44%) had normalized levels of mucosal TNF expression at the time of mucosal healing, whereas 35 of 42 (83%) had normalized IL17A expression levels, and 31 of 36 (86%) had normalized IFNG expression levels. The median time to relapse was 8months (range 4-12). Normalization of TNF gene expression predicted 20months (1-39) relapse-free survival after withdrawal of IFX compared to 5months (3-7) in the group with elevated TNF expression. Mucosal expression levels of IL17A, IL23, IFNG, TGFB, IL6 did not predict long-term remission (>12months) CONCLUSION: Normalization of mucosal TNF predicts long-term remission after discontinuation of IFX.

Cardiovascular risk factors in rural Kenyans are associated with differential age gradients, but not modified by sex or ethnicity.

BACKGROUND: The relationship between metabolic disease and the non-modifiable risk factors sex, age and ethnicity in Africans is not well-established. AIM: This study aimed to describe sex, age and ethnicity differences in blood pressure (BP) and lipid status in rural Kenyans. SUBJECTS AND METHODS: A cross-sectional study was undertaken among rural Kenyans. BP and pulse rate (PR) were measured while sitting and fasting blood samples were taken for analysis of standard lipid profile. Standard anthropometric measurements were collected. Physical activity energy expenditure was obtained objectively and lifestyle data were obtained using questionnaires. RESULTS: In total, 1139 individuals (61.0% women) participated aged 17-68 years. Age was positively associated with BP and plasma cholesterol levels. Sitting PR was negatively associated with age in women only (sex-interaction p < 0.001). Ethnicity did not modify any of the age-associations with haemodynamic or lipid outcomes. Differences in intercept between women and men were found in all parameters except for diastolic BP (p = 0.154), with men having lower HDL-C but higher values in all other cardiovascular risk factors. CONCLUSION: BP and plasma cholesterol levels increase with age at a similar gradient in men and women, but absolute levels of the majority of the risk factors were higher in men.

Hemoglobin levels and blood pressure are associated in rural black africans.

OBJECTIVES: The association between blood levels of hemoglobin (B-hgb) and blood pressure (BP) has been widely investigated in Caucasians and Asians but there is a paucity of data in rural black Africans. The objective was to investigate the association between B-hgb and BP in a rural black African population. METHODS: A cross-sectional study was conducted in three districts in Kenya (Bondo, Kitui, and Transmara) with the inclusion of participants aged ≥17 years. Background information, anthropometry, BP, B-hgb, hepatic insulin resistance (HOMA2-IR), standard lipid profile, and oral glucose tolerance test were obtained in each participant. RESULTS: Background characteristics among 1,167 participants showed that anemic and non-anemic participants differed significantly from each other as there were more women, lower body mass index and waist circumference (WC), lower degree of hepatic insulin resistance and plasma cholesterols among the anemic participants. Furthermore, anemic participants had significantly lower systolic and diastolic BP (P < 0.01) but not a significantly different prevalence of hypertension (P = 0.08). Multivariate linear regression models adjusted for-age, sex, plasma total-cholesterol, WC, Log2(HOMA2-IR), ethnicity, and smoking status-revealed that B-hgb (per mmol/l increment) was significantly associated with systolic BP (estimate: 1.18 (0.37-1.98)) and diastolic BP (estimate: 1.06 (0.54-1.57)) (P < 0.01). CONCLUSIONS: B-hgb is associated with BP in rural black Africans.

Early Detection and Treatment of Type 2 Diabetes Reduce Cardiovascular Morbidity and Mortality: A Simulation of the Results of the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Europe).

OBJECTIVE: To estimate the benefits of screening and early treatment of type 2 diabetes compared with no screening and late treatment using a simulation model with data from the ADDITION-Europe study. RESEARCH DESIGN AND METHODS: We used the Michigan Model, a validated computer simulation model, and data from the ADDITION-Europe study to estimate the absolute risk of cardiovascular outcomes and the relative risk reduction associated with screening and intensive treatment, screening and routine treatment, and no screening with a 3- or 6-year delay in the diagnosis and routine treatment of diabetes and cardiovascular risk factors. RESULTS: When the computer simulation model was programmed with the baseline demographic and clinical characteristics of the ADDITION-Europe population, it accurately predicted the empiric results of the trial. The simulated absolute risk reduction and relative risk reduction were substantially greater at 5 years with screening, early diagnosis, and routine treatment compared with scenarios in which there was a 3-year (3.3% absolute risk reduction [ARR], 29% relative risk reduction [RRR]) or a 6-year (4.9% ARR, 38% RRR) delay in diagnosis and routine treatment of diabetes and cardiovascular risk factors. CONCLUSIONS: Major benefits are likely to accrue from the early diagnosis and treatment of glycemia and cardiovascular risk factors in type 2 diabetes. The intensity of glucose, blood pressure, and cholesterol treatment after diagnosis is less important than the time of its initiation. Screening for type 2 diabetes to reduce the lead time between diabetes onset and clinical diagnosis and to allow for prompt multifactorial treatment is warranted.

Prevalence of self-reported stomach symptoms after consuming milk among indigenous Sami and non-Sami in Northern- and Mid-Norway - the SAMINOR study.

OBJECTIVE: The main purpose of this work was to identify the prevalence of self-reported stomach symptoms after consuming milk among Sami and non-Sami adults. STUDY DESIGN: A cross-sectional population-based study (the SAMINOR study). Data were collected by self-administrated questionnaires. METHOD: SAMINOR is a population-based study of health and living conditions conducted in 24 municipalities in Northern Norway during 2003 and 2004. The present study included 15,546 individuals aged between 36 and 79, whose ethnicity was categorized as Sami (33.4%), Kven (7.3%) and Norwegian majority population (57.2%). RESULTS: Sami respondents had a higher prevalence of self-reported stomach symptoms after consuming milk than the Norwegian majority population. The reporting was highest among Sami females (27.1%). Consumption of milk and dairy products (yoghurt and cheese) was high among all the ethnic groups. However, significantly more Sami than non-Sami never (or rarely) consume milk or cheese, and individuals who reported stomach symptoms after consuming milk had an significant lower intake of dairy products than those not reporting stomach symptoms after consuming dairy products. Sami reported general abdominal pain more often than the majority population. The adjusted models show a significant effect of Sami ethnicity in both men and women on self-reported stomach symptoms after consuming milk. In females, the odds ratio (OR)=1.77 (p=0.001) and in males OR=1.64 (p=0.001). CONCLUSION: Our study shows that the Sami population reported more stomach symptoms after consuming milk, suggesting a higher prevalence of milk intolerance among the Sami population than the Norwegian majority population.

[General practice plays a role in health check screening].

A Cochrane review has recently challenged the benefit of health checks. Included studies, screening procedures and treatments were however very heterogeneous and did not fulfil present days standards and most studies were done outside primary care. This review concentrates on research from health checks in Danish general practices focusing on early detection and treatment of risk factors for cardiovascular disease and diabetes. The authors recommend Danish general practitioners to offer opportunistic screening and treatment of people with diabetes and people at risk for cardiovascular disease. Future research questions are highlighted.

A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes.

The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (ß = 3.8 mmol l(-1), P = 2.5 × 10(-35)) and serum insulin (ß = 165 pmol l(-1), P = 1.5 × 10(-20)) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (ß = -0.18 mmol l(-1), P = 1.1 × 10(-6)) and fasting serum insulin (ß = -8.3 pmol l(-1), P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10(-24)). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (ß = 0.43 mmol l(-1), P = 5.3 × 10(-5)). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.

Effect of early multifactorial therapy compared with routine care on microvascular outcomes at 5 years in people with screen-detected diabetes: a randomized controlled trial: the ADDITION-Europe Study.

OBJECTIVE: To determine the benefit of multifactorial treatment on microvascular complications among people with type 2 diabetes detected by screening. RESEARCH DESIGN AND METHODS: This study was a multicenter cluster randomized controlled trial in primary care with randomization at the practice level. In four centers in Denmark; Cambridge, U.K.; the Netherlands; and Leicester, U.K., 343 general practices participated in the trial. Eligible for follow-up were 2,861 of the 3,057 people with diabetes detected by screening included in the original trial. Biomedical data on nephropathy were collected in 2,710 (94.7%) participants, retinal photos in 2,190 (76.6%), and questionnaire data on peripheral neuropathy in 2,312 (80.9%). The prespecified microvascular end points were analyzed by intention to treat. Results from the four centers were pooled using fixed-effects meta-analysis. RESULTS: Five years after diagnosis, any kind of albuminuria was present in 22.7% of participants in the intensive treatment (IT) group and in 24.4% in the routine care (RC) group (odds ratio 0.87 [95% CI 0.72-1.07]). Retinopathy was present in 10.2% of the IT group and 12.1% of the RC group (0.84 [0.64-1.10]), and severe retinopathy was present in one patient in the IT group and seven in the RC group. Neuropathy was present in 4.9% and 5.9% (0.95 [0.68-1.34]), respectively. Estimated glomerular filtration rate increased between baseline and follow-up in both groups (4.31 and 6.44 mL/min, respectively). CONCLUSIONS: Compared with RC, an intervention to promote target-driven, intensive management of patients with type 2 diabetes detected by screening was not associated with significant reductions in the frequency of microvascular events at 5 years.

Change in cardiovascular risk factors following early diagnosis of type 2 diabetes: a cohort analysis of a cluster-randomised trial.

BACKGROUND: There is little evidence to inform the targeted treatment of individuals found early in the diabetes disease trajectory. AIM: To describe cardiovascular disease (CVD) risk profiles and treatment of individual CVD risk factors by modelled CVD risk at diagnosis; changes in treatment, modelled CVD risk, and CVD risk factors in the 5 years following diagnosis; and how these are patterned by socioeconomic status. DESIGN AND SETTING: Cohort analysis of a cluster-randomised trial (ADDITION-Europe) in general practices in Denmark, England, and the Netherlands. METHOD: A total of 2418 individuals with screen-detected diabetes were divided into quartiles of modelled 10-year CVD risk at diagnosis. Changes in treatment, modelled CVD risk, and CVD risk factors were assessed at 5 years. RESULTS: The largest reductions in risk factors and modelled CVD risk were seen in participants who were in the highest quartile of modelled risk at baseline, suggesting that treatment was offered appropriately. Participants in the lowest quartile of risk at baseline had very similar levels of modelled CVD risk at 5 years and showed the least variation in change in modelled risk. No association was found between socioeconomic status and changes in CVD risk factors, suggesting that treatment was equitable. CONCLUSION: Diabetes management requires setting of individualised attainable targets. This analysis provides a reference point for patients, clinicians, and policymakers when considering goals for changes in risk factors early in the course of the disease that account for the diverse cardiometabolic profile present in individuals who are newly diagnosed with type 2 diabetes.