[Application of new glucose lowering drugs: DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors]. / Toepassing van nieuwe bloedglucoseverlagende middelen.

A comprehensive review of the literature on DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors has resulted in small changes to the medication roadmap of the type 2 diabetes mellitus standard of the Dutch College of General Practitioners. SGLT-2 inhibitors and GLP-1 receptor agonists may have benefits related to cardiovascular outcomes in patients with high cardiovascular risk, especially in those who have experienced a cardiovascular event. However, ascribing effectiveness related to cardiovascular outcomes on the basis of a single cardiovascular safety trial is premature. Metformin, sulfonylurea derivatives and insulin are still the cornerstone of type 2 diabetes mellitus treatment in primary care.

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.

Insulin monotherapy compared with the addition of oral glucose-lowering agents to insulin for people with type 2 diabetes already on insulin therapy and inadequate glycaemic control.

BACKGROUND: It is unclear whether people with type 2 diabetes mellitus on insulin monotherapy who do not achieve adequate glycaemic control should continue insulin as monotherapy or can benefit from adding oral glucose-lowering agents to the insulin therapy. OBJECTIVES: To assess the effects of insulin monotherapy compared with the addition of oral glucose-lowering agents to insulin monotherapy for people with type 2 diabetes already on insulin therapy and inadequate glycaemic control. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and reference lists of articles. The date of the last search was November 2015 for all databases. SELECTION CRITERIA: Randomised controlled clinical trials of at least two months' duration comparing insulin monotherapy with combinations of insulin with one or more oral glucose-lowering agent in people with type 2 diabetes. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated overall quality of the evidence using GRADE. We summarised data statistically if they were available, sufficiently similar and of sufficient quality. We performed statistical analyses according to the statistical guidelines in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We included 37 trials with 40 treatment comparisons involving 3227 participants. The duration of the interventions ranged from 2 to 12 months for parallel trials and two to four months for cross-over trials.The majority of trials had an unclear risk of bias in several risk of bias domains. Fourteen trials showed a high risk of bias, mainly for performance and detection bias. Insulin monotherapy, including once-daily long-acting, once-daily intermediate-acting, twice-daily premixed insulin, and basal-bolus regimens (multiple injections), was compared to insulin in combination with sulphonylureas (17 comparisons: glibenclamide = 11, glipizide = 2, tolazamide = 2, gliclazide = 1, glimepiride = 1), metformin (11 comparisons), pioglitazone (four comparisons), alpha-glucosidase inhibitors (four comparisons: acarbose = 3, miglitol = 1), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) (three comparisons: vildagliptin = 1, sitagliptin = 1, saxagliptin = 1) and the combination of metformin and glimepiride (one comparison). No trials assessed all-cause mortality, diabetes-related morbidity or health-related quality of life. Only one trial assessed patients' treatment satisfaction and showed no substantial differences between the addition of either glimepiride or metformin and glimepiride to insulin compared with insulin monotherapy.Insulin-sulphonylurea combination therapy (CT) compared with insulin monotherapy (IM) showed a MD in glycosylated haemoglobin A1c (HbA1c) of -1% (95% confidence interval (CI) -1.6 to -0.5); P < 0.01; 316 participants; 9 trials; low-quality evidence. Insulin-metformin CT compared with IM showed a MD in HbA1c of -0.9% (95% CI -1.2 to -0.5); P < 0.01; 698 participants; 9 trials; low-quality evidence. We could not pool the results of adding pioglitazone to insulin. Insulin combined with alpha-glucosidase inhibitors compared with IM showed a MD in HbA1c of -0.4% (95% CI -0.5 to -0.2); P < 0.01; 448 participants; 3 trials; low-quality evidence). Insulin combined with DPP-4 inhibitors compared with IM showed a MD in HbA1c of -0.4% (95% CI -0.5 to -0.4); P < 0.01; 265 participants; 2 trials; low quality evidence. In most trials the participants with CT needed less insulin, whereas insulin requirements increased or remained stable in participants with IM.We did not perform a meta-analysis for hypoglycaemic events because the included studies used different definitions.. In most trials the insulin-sulphonylurea combination resulted in a higher number of mild episodes of hypoglycaemia, compared to the IM group (range: 2.2 to 6.1 episodes per participant in CT versus 2.0 to 2.6 episodes per participant in IM; low-quality evidence). Pioglitazone CT also resulted in more mild to moderate hypoglycaemic episodes compared with IM (range 15 to 90 episodes versus 9 to 75 episodes, respectively; low-quality evidence. The trials that reported hypoglycaemic episodes in the other combinations found comparable numbers of mild to moderate hypoglycaemic events (low-quality evidence).The addition of sulphonylureas resulted in an additional weight gain of 0.4 kg to 1.9 kg versus -0.8 kg to 2.1 kg in the IM group (220 participants; 7 trials; low-quality evidence). Pioglitazone CT caused more weight gain compared to IM: MD 3.8 kg (95% CI 3.0 to 4.6); P < 0.01; 288 participants; 2 trials; low-quality evidence. Metformin CT was associated with weight loss: MD -2.1 kg (95% CI -3.2 to -1.1), P < 0.01; 615 participants; 7 trials; low-quality evidence). DPP-4 inhibitors CT showed weight gain of -0.7 to 1.3 kg versus 0.6 to 1.1 kg in the IM group (362 participants; 2 trials; low-quality evidence). Alpha-glucosidase CT compared to IM showed a MD of -0.5 kg (95% CI -1.2 to 0.3); P = 0.26; 241 participants; 2 trials; low-quality evidence.Users of metformin CT (range 7% to 67% versus 5% to 16%), and alpha-glucosidase inhibitors CT (14% to 75% versus 4% to 35%) experienced more gastro-intestinal adverse effects compared to participants on IM. Two trials reported a higher frequency of oedema with the use of pioglitazone CT (range: 16% to 18% versus 4% to 7% IM). AUTHORS' CONCLUSIONS: The addition of all oral glucose-lowering agents in people with type 2 diabetes and inadequate glycaemic control who are on insulin therapy has positive effects on glycaemic control and insulin requirements. The addition of sulphonylureas results in more hypoglycaemic events. Additional weight gain can only be avoided by adding metformin to insulin. Other well-known adverse effects of oral glucose-lowering agents have to be taken into account when prescribing oral glucose-lowering agents in addition to insulin therapy.

Impact of UKPDS risk estimation added to a first subjective risk estimation on management of coronary disease risk in type 2 diabetes - An observational study.

AIMS: To investigate the impact of the UKPDS risk engine on management of CHD risk in T2DM patients. METHODS: Observational study among 139 GPs. Data from 933 consecutive patients treated with a maximum of two oral glucose lowering drugs, collected at baseline and after twelve months. GPs estimated the CHD risk themselves and afterwards they calculated this with the UKPDS risk engine. Under- and overestimation were defined as a difference >5 percentage points difference between both calculations. The impact of the UKPDS risk engine was assessed by measuring differences in medication adjustments between the over-, under- and accurately estimated group. RESULTS: In 42.0% the GP accurately estimated the CHD risk, in 32.4% the risk was underestimated and in 25.6% overestimated. Mean difference between the estimated (18.7%) and calculated (19.1%) 10 years CHD risk was -0.36% (95% CI -1.24 to 0.52). Male gender, current smoking and total cholesterol level were associated with underestimation. Patients with an subjectively underestimated CHD risk received significantly more medication adjustments. Their UKPDS 10 year CHD risk did not increase during the follow-up period, contrary to the other two groups of patients. CONCLUSIONS: The UKPDS risk engine may be of added value for risk management in T2DM.

New oral anticoagulants for nonvalvular atrial fibrillation in the elderly: Limited applicability in primary care.

BACKGROUND: Based on the results from randomized controlled trials (RCTs), new oral anticoagulants (NOACs) seem attractive alternatives to vitamin K antagonists (VKAs) because of their effectiveness, safety, and ease of use. However, the use of NOACs in unselected elderly patients with atrial fibrillation (AF) in primary care is arguable. OBJECTIVES: To assess the evidence for the effectiveness and safety of NOACs compared with VKAs in elderly patients with nonvalvular AF in primary care. METHODS: Starting from the meta-analysis of Ruff et al. (Lancet 2014;383:955-62), we used the GRADE-approach to make a transparent and explicit judgement of the quality of evidence. RESULTS: The meta-analysis reviewed four non-inferiority RCTs, including 58 634 AF patients with an average age of 70-73 years. Inconsistency of results, indirectness of evidence, and imprecision of risk reductions resulted in downgrading of the quality of evidence available from these studies. The quality of evidence for a decrease in all-cause stroke and systemic embolism (RR: 0.81; 95%CI: 0.73-0.91) for elderly patients using NOACs compared to VKAs in routine primary care was low. The quality of evidence for a lower risk for haemorrhagic stroke (RR: 0.49; 95% CI: 0.38-0.64) and for a lower risk of intracranial bleeding (RR: 0.48; 95% CI: 0.39-0.59) was moderate. CONCLUSION: There is uncertainty about effectiveness and safety of NOACs in unselected elderly patients with AF in primary care. Therefore, the balance between benefit and harm is still unclear. For this reason, routine use of NOACs is not recommended in elderly patients in primary care.

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.

[Important changes in the Dutch College of General Practitioners (NHG) practice guideline 'Atrial fibrillation': revised practice guideline issued]. / Belangrijke wijzigingen in de NHG-standaard 'Atriumfibrilleren': herziene versie verschenen.

A small number of points in the NHG practice guideline 'Atrial fibrillation' have been reviewed; this has important consequences for general practice. The risk of ischaemic CVA in patients with atrial fibrillation is determined using a new risk score (CHA2DS2-VASc). The target value of the resting ventricular frequency has been increased from a maximum of 90 to a maximum of 110 beats per minute. Oral anticoagulants are indicated in almost all patients aged 65 years and older with atrial fibrillation; the only group in whom antithrombotic medication is not indicated is men under the age of 75 with no cardiovascular comorbidity. Acetylsalicylic acid for the prevention of thrombo-embolism is only indicated if oral anticoagulants are contra-indicated. The new oral anticoagulants (NOACs) have very limited use in the prevention of a thrombo-embolism in general practice.

Effect of early intensive multifactorial therapy compared with routine care on self-reported health status, general well-being, diabetes-specific quality of life and treatment satisfaction in screen-detected type 2 diabetes mellitus patients (ADDITION-Europe): a cluster-randomised trial.

AIMS/HYPOTHESIS: The study aimed to examine the effects of intensive treatment (IT) vs routine care (RC) on patient-reported outcomes after 5 years in screen-detected diabetic patients. METHODS: In a pragmatic, cluster-randomised, parallel-group trial, 343 general practices in Denmark, Cambridge and Leicester (UK) and the Netherlands were randomised to screening for type 2 diabetes mellitus plus IT of multiple risk factors in people 40-69 years without known diabetes (n = 1,678 patients) or screening plus RC (n = 1,379 patients). Practices were randomised in a 1:1 ratio according to a computer-generated list. Diabetes mellitus was diagnosed according to WHO criteria. Exclusions were: life expectancy <1 year, housebound, pregnant or lactating, or psychological or psychiatric problems. Treatment targets for IT were: HbA1c <7.0% (53 mmol/mol), BP ≤135/85 mmHg, cholesterol <5 mmol/l in the absence of a history of coronary heart disease and <4.5 mmol/l in patients with cardiovascular (CV) disease; prescription of aspirin to people taking antihypertensive medication and, in cases of CV disease or BP >120/80 mmHg, ACE inhibitors were recommended. After 2003, the treatment algorithm recommended statins to all patients with cholesterol of ≥3.5 mmol/l. Outcome measures were: health status (Euroqol 5 Dimensions [EQ-5D]) at baseline and at follow-up; and health status (36-item Short Form Health Survey [SF-36] and Euroquol Visual Analogue Scale [EQ-VAS]), well-being (12-item Short Form of the Well-Being Questionnaire), diabetes-specific quality of life (Audit of Diabetes-Dependent Quality of Life) and satisfaction with diabetes treatment (Diabetes Treatment Satisfaction Questionnaire) at follow-up. At baseline, standardised self-report questionnaires were used to collect information. Questionnaires were completed at the same health assessment visit as the anthropometric and biochemical measurements. The patients and the staff assessing the outcomes were unaware of the group assignments. Participants were followed for a mean of 5.7 years. Outcome data were available for 1,250 participants in the intensive treatment group (74%) and 967 participants in the routine care group (70%). The estimated differences in means from the four centres were pooled using random effects meta-analysis. Baseline EQ-5D level was used as a covariate in all analyses. RESULTS: EQ-5D values did not change between diagnosis and follow-up, with a median (interquartile range) of 0.85 (0.73-1.00) at baseline and 0.85 (0.73-1.00) at 5 year follow-up. Health status, well-being, diabetes-specific quality of life and treatment satisfaction did not differ between the intensive treatment and routine care groups. There was some heterogeneity between centres (I 2 being between 13% [SF-36 physical functioning] and 73% [EQ-VAS]). CONCLUSIONS/INTERPRETATION: There were no differences in health status, well-being, quality of life and treatment satisfaction between screen-detected type 2 diabetes mellitus patients receiving intensive treatment and those receiving routine care. These results suggest that intensive treatment does not adversely affect patient-reported outcomes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00237549 FUNDING: ADDITION-Denmark was supported by the National Health Services, the Danish Council for Strategic Research, the Danish Research Foundation for General Practice, Novo Nordisk Foundation, the Danish Centre for Evaluation and Health Technology Assessment, the Diabetes Fund of the National Board of Health, the Danish Medical Research Council and the Aarhus University Research Foundation. In addition, unrestricted grants from pharmaceutical companies were received. ADDITION-Cambridge was supported by the Wellcome Trust, the Medical Research Council, the NIHR Health Technology Assessment Programme, National Health Service R&D support funding and the National Institute for Health Research. SJG received support from the Department of Health NIHR grant funding scheme. ADDITION-Leicester was supported by Department of Health, the NIHR Health Technology Assessment Programme, National Health Service R&D support funding and the National Institute for Health Research. ADDITION-Netherlands was supported by unrestricted grants from Novo Nordisk, Glaxo Smith Kline and Merck, and by the Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht.

Work stress, sense of coherence, and risk of type 2 diabetes in a prospective study of middle-aged Swedish men and women.

OBJECTIVE: To investigate the prospective influence of work stress on type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: This population-based cohort included 3,205 women and 2,227 men, aged 35-56 years, with baseline normal glucose tolerance measured with oral glucose tolerance test. At follow-up 8-10 years later, T2D was diagnosed in 60 women and 111 men. Work stress factors evaluated by questionnaire (i.e., demands, decision latitude, job strain, shift work, overtime work, and also sense of coherence) were studied in association with T2D. Odds ratios (ORs) and 95% CIs adjusted for age, education, BMI, physical activity, smoking, family history of diabetes, and psychological distress were calculated. RESULTS: In women, low decision latitude was associated with T2D on its own (OR 2.4 [95% CI 1.1-5.2]) and combined with high demands: job strain (OR 4.2 [2.0-8.7]), adjusted for all available potential confounders. Also, shift work increased the risk of T2D in women (OR 2.2 [1.0-4.7]) when adjusted for age, education, and psychological distress, although this risk was diluted after multifactor adjustment (OR 1.9 [0.8-4.4]). In men, high work demands and high strain decreased the risk of T2D (OR 0.5 [0.3-0.9]) for both measures, as did an active job (high demands and high decision latitude, OR 0.4 [0.2-0.9]). CONCLUSIONS: Work stress and shift work may contribute to the development of T2D in women. In men, the risk was decreased by high work demands, high strain, and an active job.

[Summary of the NHG practice guideline 'Lower urinary tract symptoms in men']. / Samenvatting van de NHG-standaard 'Mictieklachten bij mannen'.

In general practice, lower urinary tract symptoms (LUTS) in men are usually not attributable to specific disorders. Prostate cancer is rarely the cause of LUTS. Education, counselling, and non-pharmaceutical advice form the basis for treatment of LUTS. Only when these measures do not relieve the patient's symptoms sufficiently, drug therapy could be considered. Alpha-blockers are the drugs of first choice and are also recommended when transurethral catheterization is needed for acute urinary retention. The effect of medication on LUTS is limited and largely based on placebo effect. The effectiveness of prostate cancer screening is a subject of debate; therefore patients asking for a PSA test should be informed about the benefits and harms of measuring PSA before having a test. A PSA value > 4 ng/ml, or abnormal results on digital rectal examination should prompt further diagnostic evaluation.

Computerized decision support systems in primary care for type 2 diabetes patients only improve patients' outcomes when combined with feedback on performance and case management: a systematic review.

PURPOSE: Computerized decision support systems (CDSSs) are often part of a multifaceted intervention to improve diabetes care. We reviewed the effects of CDSSs alone or in combination with other supportive tools in primary care for type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A systematic literature search was conducted for January 1990-July 2011 in PubMed, Embase, and the Cochrane Database and by consulting reference lists. Randomized controlled trials (RCTs) in general practice were selected if the interventions consisted of a CDSS alone or combined with a reminder system and/or feedback on performance and/or case management. The intervention had to be compared with usual care. Two pairs of reviewers independently abstracted all available data. The data were categorized by process of care and patient outcome measures. RESULTS: Twenty RCTs met inclusion criteria. In 14 studies a CDSS was combined with another intervention. Two studies were left out of the analysis because of low quality. Four studies with a CDSS alone and four studies with a CDSS and reminders showed improvements of the process of care. CDSS with feedback on performance with or without reminders improved the process of care (one study) and patient outcome (two studies). CDSS with case management improved patient outcome (two studies). CDSS with reminders, feedback on performance, and case management improved both patient outcome and the process of care (two studies). CONCLUSIONS: CDSSs used by healthcare providers in primary T2DM care are effective in improving the process of care; adding feedback on performance and/or case management may also improve patient outcome.

Remission of screen-detected metabolic syndrome and its determinants: an observational study.

BACKGROUND: Early detection and treatment of the metabolic syndrome may prevent diabetes and cardiovascular disease. Our aim was to assess remission of the metabolic syndrome and its determinants after a population based screening without predefined intervention in the Netherlands. METHODS: In 2006 we detected 406 metabolic syndrome cases (The National Cholesterol Education Program's Adult Treatment Panel III (NCEP ATP III) definition) among apparently healthy individuals with an increased waist circumference. They received usual care in a primary care setting. After three years metabolic syndrome status was re-measured. We evaluated which baseline determinants were independently associated with remission. RESULTS: The remission rate among the 194 participants was 53%. Baseline determinants independently associated with a remission were the presence of more than three metabolic syndrome components (OR 0.46) and higher levels of waist circumference (OR 0.91), blood pressure (OR 0.98) and fasting glucose (OR 0.60). CONCLUSIONS: In a population with screen-detected metabolic syndrome receiving usual care, more than half of the participants achieved a remission after three years. This positive result after a relatively simple strategy provides a solid basis for a nation-wide implementation. Not so much socio-demographic variables but a higher number and level of the metabolic syndrome components were predictors of a lower chance of remission. In such cases, primary care physicians should be extra alert.

Advanced glycation end products measured by skin autofluorescence in a population with central obesity.

Accumulation of advanced glycation end products (AGEs) is enhanced by chronic hyperglycemia and oxidative stress and this process may contribute to the pathogenesis of vascular disease. Skin autofluorescence (AF), a measure of accumulation of AGEs in skin collagen, is associated with vascular disease in patients with diabetes.   Because central obesity enhances oxidative stress people with central obesity might already have increased accumulation of AGEs before diabetes or cardiovascular disease become manifest. To test this hypothesis, we compared the distribution of skin AF and its association with clinical and biochemical parameters in individuals with and without central obesity. Skin AF was measured by a validated AGE Reader in 816 persons with and 431 persons without central obesity, aged 20-70 y. Mean skin AF increased with age and smoking and was higher in centrally obese individuals compared with non-obese individuals (p = 0.001, after adjustment for age and smoking p = 0.13). Mean skin AF in the subgroups without central obesity and without other risk factors (n = 106), central obesity without other risk factors (n = 74) and central obesity with other risk factors (n = 742) was 1.63 ± 0.37, 1.74 ± 0.44 and 1.87 ± 0.43 AU, respectively (p for trend < 0.001, after adjustment for age and smoking p for trend = 0.12). In the group with central obesity age, current smoking, alcohol consumption, waist circumference, creatinine clearance and hs-CRP were independently associated with skin AF (R(2) = 29.4%). Waist circumference hardly contributed to the explained variance. The relationship between waist circumference and skin AF is not as obvious as we hypothesized.

High-sensitivity C-reactive protein to detect metabolic syndrome in a centrally obese population: a cross-sectional analysis.

BACKGROUND: People with central obesity have an increased risk for developing the metabolic syndrome, type 2 diabetes and cardiovascular disease. However, a substantial part of obese individuals have no other cardiovascular risk factors, besides their obesity. High sensitivity C-reactive protein (hs-CRP), a marker of systemic inflammation and a predictor of type 2 diabetes and cardiovascular disease, is associated with the metabolic syndrome and its separate components. We evaluated the use of hs-CRP to discriminate between centrally obese people with and without the metabolic syndrome. METHODS: 1165 people with central obesity but without any previous diagnosis of hypertension, dyslipidemia, diabetes or cardiovascular disease, aged 20-70 years, underwent a physical examination and laboratory assays to determine the presence of the metabolic syndrome (NCEP ATP III criteria). Multivariable linear regression analyses were performed to assess which metabolic syndrome components were independently associated with hs-CRP. A ROC curve was drawn and the area under the curve was calculated to evaluate whether hs-CRP was capable to predict the presence of the metabolic syndrome. RESULTS: Median hs-CRP levels were significantly higher in individuals with central obesity with the metabolic syndrome (n = 417; 35.8%) compared to individuals with central obesity without the metabolic syndrome (2.2 mg/L (IQR 1.2-4.0) versus 1.7 mg/L (IQR 1.0-3.4); p < 0.001). Median hs-CRP levels increased with an increasing number of metabolic syndrome components present. In multivariable linear regression analyses, waist circumference and triglycerides were the only components that were independently associated with hs-CRP after adjusting for smoking, gender, alcohol consumption and the other metabolic syndrome components. The area under the ROC curve was 0.57 (95%-CI 0.53-0.60). CONCLUSIONS: Hs-CRP has limited capacity to predict the presence of the metabolic syndrome in a population with central obesity.

Intensive multifactorial treatment and cognitive functioning in screen-detected type 2 diabetes--the ADDITION-Netherlands study: a cluster-randomized trial.

AIM: To assess whether an intensive multifactorial treatment can reduce cognitive decrements and cognitive decline in screen-detected type 2 diabetes. METHODS: The multinational ADDITION-study, a cluster-randomized parallel group trial in patients with screen-detected type 2 diabetes, compared the effectiveness of intensive multifactorial treatment (IT; lifestyle advice and strict regulation of metabolic parameters) with routine care (RC) on cardiovascular outcome. In The Netherlands randomization was stratified according to practice organization. Allocation was concealed from patients. The present study assessed the effect of IT on cognition through two neuropsychological assessments (NPA) on two occasions. The assessments took place three and six years after the start of the intervention. Non-diabetic controls served as reference group. The first NPA was performed in 183 patients (IT: 97; RC: 86) and 69 controls. The second NPA was performed in 135 patients (IT: 71; RC: 64) and 55 controls. Primary outcome was a composite score, including the domains memory, information-processing speed and attention and executive function. Comparisons between the treatment groups were performed with multi-level analyses. RESULTS: The first NPA showed no differences between the treatment groups (mean difference composite z-score: 0.00; 95%-CI -0.16 to 0.16; IT vs RC). Over the next three years cognitive decline in the diabetic groups was within the range of the reference group and did not differ between the treatment arms (difference decline between diabetic groups -0.12; -0.24 to 0.01; IT vs RC). CONCLUSIONS: Six years of IT in screen-detected type 2 diabetes had no benefit on cognitive functioning over RC.

Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial.

BACKGROUND: Intensive treatment of multiple cardiovascular risk factors can halve mortality among people with established type 2 diabetes. We investigated the effect of early multifactorial treatment after diagnosis by screening. METHODS: In a pragmatic, cluster-randomised, parallel-group trial done in Denmark, the Netherlands, and the UK, 343 general practices were randomly assigned screening of registered patients aged 40-69 years without known diabetes followed by routine care of diabetes or screening followed by intensive treatment of multiple risk factors. The primary endpoint was first cardiovascular event, including cardiovascular mortality and morbidity, revascularisation, and non-traumatic amputation within 5 years. Patients and staff assessing outcomes were unaware of the practice's study group assignment. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00237549. FINDINGS: Primary endpoint data were available for 3055 (99·9%) of 3057 screen-detected patients. The mean age was 60·3 (SD 6·9) years and the mean duration of follow-up was 5·3 (SD 1·6) years. Improvements in cardiovascular risk factors (HbA(1c) and cholesterol concentrations and blood pressure) were slightly but significantly better in the intensive treatment group. The incidence of first cardiovascular event was 7·2% (13·5 per 1000 person-years) in the intensive treatment group and 8·5% (15·9 per 1000 person-years) in the routine care group (hazard ratio 0·83, 95% CI 0·65-1·05), and of all-cause mortality 6·2% (11·6 per 1000 person-years) and 6·7% (12·5 per 1000 person-years; 0·91, 0·69-1·21), respectively. INTERPRETATION: An intervention to promote early intensive management of patients with type 2 diabetes was associated with a small, non-significant reduction in the incidence of cardiovascular events and death. FUNDING: National Health Service Denmark, Danish Council for Strategic Research, Danish Research Foundation for General Practice, Danish Centre for Evaluation and Health Technology Assessment, Danish National Board of Health, Danish Medical Research Council, Aarhus University Research Foundation, Wellcome Trust, UK Medical Research Council, UK NIHR Health Technology Assessment Programme, UK National Health Service R&D, UK National Institute for Health Research, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, Novo Nordisk, Astra, Pfizer, GlaxoSmithKline, Servier, HemoCue, Merck.

[Detection of metabolic syndrome by self-measurement of waist circumference]. / Opsporing van het metabool syndroom door mensen zelf hun middelomtrek te laten meten.

OBJECTIVE: Determination of both the feasibility and the result in terms of cardiovascular risk factors of self-measurement of waist circumference by apparently healthy people. We also investigated the prevalence of metabolic syndrome in a population of patients aged 20-69 years in IJsselstein, the Netherlands. DESIGN: Cross-sectional survey. METHODS: All patients aged 20-69 years in the care of a group of General Practitioners (GPs) in IJsselstein, the Netherlands, who were not known to have diabetes, hypertension or dyslipidaemia (n = 11,862), received a tape measure and instructions by mail with the request to measure their waist circumference. Those with an increased waist circumference (> 88 and > 102 cm for women and men, respectively) were invited to undergo investigations to determine whether they conformed to the NCEP ATP III criteria for metabolic syndrome. The prevalence of metabolic syndrome was determined by a combination of these results with file studies of those with already known risk factors for cardiac and vascular disease. RESULTS: The total response rate was 62%. The intraclass correlation between the waist circumference measured by the respondents and by the investigators was 0.80 (p < 0.05). 473 new cases of metabolic syndrome were detected among 1721 persons with an increased waist circumference on self-measurement, 40 % in people younger than 45 years. The total prevalence among those aged 20-69 years in IJsselstein was 15.5%. Only 39% of the people with the metabolic syndrome were already known to have risk factors. CONCLUSIONS: A GP initiated screening system for metabolic syndrome, in which self-measurement of waist circumference was the first step, proved to be feasible and reliable. A substantial group of people aged less than 45 years and at increased cardiovascular risk were also detected using this method of population screening.

Towards a more efficient diabetes control in primary care: six-monthly monitoring compared with three-monthly monitoring in type 2 diabetes - The EFFIMODI trial. Design of a randomised controlled patient-preference equivalence trial in primary care.

BACKGROUND: Scientific evidence for the frequency of monitoring of type 2 diabetes patients is lacking. If three-monthly control in general practice could be reduced to six-monthly control in some patients, this would on the one hand reduce the use of medical services including involvement of practice nurses, and thus reduce costs, and on the other hand alleviate the burden of people with type 2 diabetes. The goal of this study is to make primary diabetes care as efficient as possible for patients and health care providers. Therefore, we want to determine whether six-monthly monitoring of well-controlled type 2 diabetes patients in primary care leads to equivalent cardiometabolic control compared to the generally recommended three-monthly monitoring. METHODS AND DESIGN: The study is a randomised controlled patient-preference equivalence trial. Participants are asked if they prefer three-monthly (usual care) or six-monthly diabetes monitoring. If they do not have a preference, they are randomised to a three-monthly or six-monthly monitoring group. Patients are eligible for the study if they are between 40 and 80 years old, diagnosed with type 2 diabetes more than one year ago, treated by a general practitioner, not on insulin treatment, and with HbA1c < or = 7.5%, systolic blood pressure < or = 145 mmHg and total cholesterol < or = 5.2 mmol/l. The intervention group (six-monthly monitoring) will receive the same treatment with the same treatment targets as the control group (three-monthly monitoring). The intervention period will last one and a half year. After the intervention, the three-monthly and six-monthly monitoring groups are compared on equivalence of cardiometabolic control. Secondary outcome measures are HbA1c, blood pressure, cholesterol level, Body Mass Index, smoking behaviour, physical activity, loss of work due to illness, health status, diabetes-specific distress, satisfaction with treatment and adherence to medications. We will use intention-to-treat analysis with repeated measures. For outcomes that have only baseline and final measurements, we will use ANCOVA. Depending on the results, a cost-minimisation analysis or an incremental cost-effectiveness analysis will be done. DISCUSSION: This study will provide valuable information on the most efficient control frequency of well-controlled type 2 diabetes patients in primary care.

No negative effects of a multi-factorial, intensified treatment on self-reported health status, treatment satisfaction, and diabetes-related distress in screen-detected type 2 diabetes patients. The ADDITION-Netherlands study.

PURPOSE: To examine the effects of a multi-factorial, intensified treatment on self-reported health status, treatment satisfaction, and diabetes-related distress in screen-detected type 2 diabetes patients. METHODS: Cluster-randomised controlled trial; A total of 498 screen-detected type 2 diabetes patients from 79 general practices were assigned to intensified (n = 255) or routine treatment according to Dutch guidelines (n = 243). At baseline and after 3 years, patients completed the Short Form-36 and the European Quality of Life-5 Dimensions questionnaires. After 4.5 years, patients completed the Diabetes Treatment Satisfaction Questionnaire and the Problem Areas In Diabetes scale. We analysed the effects of intensified treatment on self-rated health status, treatment satisfaction, and diabetes-related distress, using random effects models to account for clustering at practice level. RESULTS: Three to 5 years after type 2 diabetes was detected by screening, there were no differences between intensified and routine treatment in self-reported health status, treatment satisfaction, and diabetes-related distress. CONCLUSIONS: Multi-factorial, intensified treatment did not influence self-rated health status, treatment satisfaction, and distress in screen-detected type 2 diabetes patients. Therefore, health care professionals do not have to fear negative effects of an intensified treatment on these psychological outcomes.