Niels de Fine Olivarius

Randomised controlled trial of structured personal care of type 2 diabetes mellitus

Abstract Objective: To assess the effect of a multifaceted intervention directed at general practitioners on six year mortality, morbidity, and risk factors of patients with newly diagnosed type 2 diabetes. Design: Pragmatic, open, controlled trial with randomisation of practices to structured personal care or routine care; analysis after 6 years. Setting: 311 Danish practices with 474 general practitioners (243 in intervention group and 231 in comparison group). Participants: 874 (90.1%) of 970 patients aged ≥40 years who had diabetes diagnosed in 1989-91 and survived until six year follow up. Intervention: Regular follow up and individualised goal setting supported by prompting of doctors, clinical guidelines, feedback, and continuing medical education. Main outcome measures: Predefined clinical non-fatal outcomes, overall mortality, risk factors, and weight. Results: Predefined non-fatal outcomes and mortality were the same in both groups. The following risk factor levels were lower for intervention patients than for comparison patients (median values): fasting plasma glucose concentration (7.9 v 8.7 mmol/l, P=0.0007), glycated haemoglobin (8.5% v 9.0%, P<0.0001; reference range 5.4-7.4%), systolic blood pressure (145 v 150 mm Hg, P=0.0004), and cholesterol concentration (6.0 v 6.1 mmol/l, P=0.029, adjusted for baseline concentration). Both groups had lost weight since diagnosis (2.6 v 2.0 kg). Metformin was the only drug used more frequently in the intervention group (24% (110/459) v 15% (61/415)).Intervention doctors arranged more follow up consultations, referred fewer patients to diabetes clinics, and set more optimistic goals. Conclusions: In primary care, individualised goals with educational and surveillance support may for at least six years bring risk factors of patients with type 2 diabetes to a level that has been shown to reduce diabetic complications but without weight gain. What is already known on this topic Evidence is increasing that control of hyperglycaemia, hypertension, and dyslipidaemia may postpone the development of diabetic complications in patients with type 2 diabetes Maintaining good control over a long period can be difficult What this study adds Structured individualised personal care with educational and surveillance support for general practitioners reduced levels of risk factors in type 2 diabetic patients after six years Risk factors were reduced to a level that has been shown to have a beneficial effect on diabetic complications Participants also showed modest weight loss

The Danish National Health Service Register

Introduction: To describe the Danish National Health Service Register in relation to research. Content: The register contains data collected for administrative and scientific purposes from health contractors in primary health care. It includes information about citizens, providers, and health services but minimal clinical information. Validity and coverage: The register covers everyone living in Denmark and data is available from 1990. No validity studies have been reported. Because the data is connected to reimbursement the coverage is assumed to be good. Conclusion: The strengths of the register include completeness, size, and long follow-up period. It is useful for research purposes but reservations must be made regarding its validity.

Urinary Markers of Nucleic Acid Oxidation and Long-Term Mortality of Newly Diagnosed Type 2 Diabetic Patients

OBJECTIVE We analyzed data from a cohort of 1,381 newly diagnosed type 2 diabetic patients to test the hypothesis that urinary markers of nucleic acid oxidation are independent predictors of mortality. RESEARCH DESIGN AND METHODS We examined the relationship between urinary excretion of markers of DNA oxidation (8-oxo-7,8-dihydro-2′-deoxyguanosine [8-oxodG]) and RNA oxidation (8-oxo-7,8-dihydroguanosine [8-oxoGuo]) and long-term mortality using Cox proportional hazards regression. RESULTS After multivariate adjustment, the hazard ratios for all-cause and diabetes-related mortality of patients with 8-oxoGuo levels in the highest quartile compared with those in the lowest quartile were 1.44 (1.12–1.85) and 1.54 (1.13–2.10), respectively. Conversely, no significant associations between 8-oxodG and mortality were found in the adjusted analyses. CONCLUSIONS Urinary excretion of the RNA oxidation marker 8-oxoGuo measured shortly after diagnosis of type 2 diabetes predicts long-term mortality independently of conventional risk factors. This finding suggests that 8-oxoGuo could serve as a new clinical biomarker in diabetes.

Frequency of spontaneously occurring postmenopausal bleeding in the general population

Background.  To determine the frequency of spontaneously occurring postmenopausal bleeding in the population, a prospective observational population study was undertaken.

Association between urinary markers of nucleic acid oxidation and mortality in type 2 diabetes: a population-based cohort study.

OBJECTIVE We recently showed that RNA oxidation, estimated by urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo), independently predicted mortality in a cohort of 1,381 treatment-naive patients with newly diagnosed type 2 diabetes. In the present investigation, we analyzed urine collected 6 years after the diagnosis to assess the association between urinary markers of nucleic acid oxidation and mortality in patients with established and treated diabetes. RESEARCH DESIGN AND METHODS We used data from the 970 patients who attended the screening for diabetes complications 6 years after the diagnosis. Cox proportional hazards regression was used to examine the relationship between urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2′-deoxyguanosine [8-oxodG] [n = 938]) and RNA oxidation (8-oxoGuo [n = 936]) and mortality. RESULTS During a median of 9.8 years of follow-up, 654 patients died. Urinary 8-oxoGuo assessed 6 years after the diagnosis was significantly associated with mortality. The multivariate-adjusted hazard ratios for all-cause and diabetes-related mortality of patients with 8-oxoGuo levels in the highest quartile compared with those in the lowest quartile were 1.86 (95% CI 1.34–2.58) and 1.72 (1.11–2.66), respectively. Conversely, 8-oxodG was not associated with mortality. In addition, we found an association between changes in 8-oxoGuo from diagnosis to 6-year follow-up and mortality, with increased risk in patients with an increase and decreased risk in patients with a decrease in 8-oxoGuo. CONCLUSIONS The RNA oxidation marker 8-oxoGuo is an independent predictor of mortality in patients with established and treated type 2 diabetes, and changes in 8-oxoGuo during the first 6 years after diagnosis are associated with mortality.

Consequences Of Bias and Imprecision in Measurements of Glucose and Hba1c for the Diagnosis and Prognosis of Diabetes Mellitus

Aim: To investigate the effect of composite analytical bias and imprecision in the measurements of fasting plasma‐glucose (fPG) for diagnosis of diabetes mellitus and estimation of risk of development and progression of retinopathy using measurements of Haemoglobin A1C (HbA1C%). Materials and methods: Data on biological within‐subject variation for fPG (5.7% and 4.9%) and HbA1C% (1.9%) from literature and data on fPG for a ‘low‐risk’ population (regarding diabetes) from own investigations (ln‐values of mean=1.6781∼geometric mean population=5.36 mmol/L and standard deviation=0.0891∼CV population=8.9%). Further, guidelines for diagnosis of diabetes (two consecutive measurements of fPG above 7.0 mmol/L) were obtained from literature as also the risk of development of and progression of retinopathy using measurements of HbA1C (a change in risk of 44% for a change in HbA1C% of 10%). It was assumed that each individual had values which over a short time had a Gaussian distribution about a biological set‐point. Calculations of the effect of analytical bias and imprecision were performed by linear addition of bias and squared addition of imprecision to the squared error‐free biological distribution. Composite variations of bias and imprecision were obtained by varying assumed imprecision and calculating the maximum acceptable bias for the stated situation. Results: Two diagnostic examples are described for fPG and one for risk related to HbA1C%. Firstly, the risk of diabetes as a function of set‐point and bias and imprecision was investigated, using functions where the probability of two measurements above 7.0 mmol/L was plotted against biological set‐points, resulting in a S‐shaped curve with a 25% probability for a set‐point equal to 7.0 mmol/L. Here, a maximum 5% probability of classifying an individual with a set‐point of 6.4 mmol/L (upper reference limit for the ‘low‐risk’ population) as diabetic was used to calculate the analytical quality specifications. Comparably, the 5% probability of misclassifying a diabetic with fPG of 8.0 mmol/L was investigated, and both specifications were illustrated in an imprecision‐bias plot. Secondly, the percentage of ‘low‐risk’ individuals which would be falsely diagnosed as diabetic was calculated, and this percentage was plotted as a function of bias for different assumed values of imprecision. Thirdly, the confidence intervals for a certain risk‐difference for HbA1C% of 5% or 10% was used to draw an imprecision‐bias plot for different assumed changes and probabilities. Discussion: Analytical quality taking the demands for bias and imprecision in account are obtainable in laboratories, but may be questionable for use of capillary blood and POCT instruments with considerable consequences for the number of individuals classified as diabetics, and thereby for the economy etc. Conclusion: For clinical settings, with so clear recommendations and descriptions of risk curves as in diabetes, it is relatively easy to estimate the analytical quality specifications according to the highest level of the model hierarchy, when relevant probabilities for the events are assumed.

The relationship between HbA1c level, symptoms and self-rated health in type 2 diabetic patients

Abstract Objective. Improving glycaemic control is generally supposed to reduce symptoms experienced by type 2 diabetic patients, but the relationships between glycated haemoglobin (HbA1c), diabetes-related symptoms, and self-rated health (SRH) are unclarified. This study explored the relationships between these aspects of diabetes control. Design. A cross-sectional study one year after diagnosis of type 2 diabetes. Subjects. A population-based sample of 606 type 2 diabetic patients, median age 65.6 years at diagnosis, regularly reviewed in primary care. Main outcome measures. The relationships between HbA1c, diabetes-related symptoms, and SRH. Results. The patients’ median HbA1c was 7.8 (reference interval: 5.4–7.4 % at the time of the study). 270 (45.2%) reported diabetes-related symptoms within the past 14 days. SRH was associated with symptom score (γ = 0.30, p < 0.001) and HbA1c (γ = 0.17, p = 0.038) after correction for covariates. The relation between HbA1c and symptom score was explained by SRH together with other confounders, e.g. hypertension (γ = 0.02, p = 0.40). The relation between the symptom fatigue and SRH was not explained by symptom score and significantly modified the direct association between symptom score and SRH. Conclusions. Symptom relief may not occur even when HbA1c level is at its lowest average level in the natural history of diabetes, and symptoms and SRH are closely linked. Monitoring symptoms in the clinical encounter to extend information on disease severity, as measured e.g. by HbA1c, may help general practitioners and patients to understand the possible impact of treatments and of disease manifestations in order to obtain optimum disease control.

The role of diseases, risk factors and symptoms in the definition of multimorbidity – a systematic review

Abstract Objective is to explore how multimorbidity is defined in the scientific literature, with a focus on the roles of diseases, risk factors, and symptoms in the definitions. Design: Systematic review. Methods: MEDLINE (PubMed), Embase, and The Cochrane Library were searched for relevant publications up until October 2013. One author extracted the information. Ambiguities were resolved, and consensus reached with one co-author. Outcome measures were: cut-off point for the number of conditions included in the definitions of multimorbidity; setting; data sources; number, kind, duration, and severity of diagnoses, risk factors, and symptoms. We reviewed 163 articles. In 61 articles (37%), the cut-off point for multimorbidity was two or more conditions (diseases, risk factors, or symptoms). The most frequently used setting was the general population (68 articles, 42%), and primary care (41 articles, 25%). Sources of data were primarily self-reports (56 articles, 42%). Out of the 163 articles selected, 115 had individually constructed multimorbidity definitions, and in these articles diseases occurred in all definitions, with diabetes as the most frequent. Risk factors occurred in 98 (85%) and symptoms in 71 (62%) of the definitions. The severity of conditions was used in 26 (23%) of the definitions, but in different ways. The definition of multimorbidity is heterogeneous and risk factors are more often included than symptoms. The severity of conditions is seldom included. Since the number of people living with multimorbidity is increasing there is a need to develop a concept of multimorbidity that is more useful in daily clinical work. Key Points The increasing number of multimorbidity patients challenges the healthcare system. The concept of multimorbidity needs further discussion in order to be implemented in daily clinical practice. Many definitions of multimorbidity exist and most often a cut-off point of two or more is applied to a range of 4–147 different conditions. Diseases are included in all definitions of multimorbidity. Risk factors are often included in existing definitions, whereas symptoms and the severity of the conditions are less frequently included.

16-year excess all-cause mortality of newly diagnosed type 2 diabetic patients: a cohort study

BackgroundStudies have shown that type 2 diabetic patients have higher all-cause mortality than people without diabetes, but it is less clear how diabetes affects mortality in elderly patients and to what degree mortality differs between diabetic men and women. The aim of the present study is to investigate the age- and sex-specific all-cause mortality pattern in patients with type 2 diabetes in comparison with the Danish background population.MethodsPopulation-based cohort study of 1323 patients, diagnosed with clinical type 2 diabetes in 1989-92 and followed for 16 years. Median (interquartile range) age at diagnosis was 65.3 (55.8-73.6) years. The age- and sex-specific hazard rates were estimated for the cohort using the life table method and compared with the expected hazard rates calculated with Danish register data from the general population.ResultsIn comparison with the general population, diabetic patients had a 1.5-2.5 fold higher risk of dying depending on age. The over-mortality was higher for men than for women. It decreased with age in both sexes, and among patients over 80 years at diagnosis the difference between the observed and the expected survival was small.ConclusionWe found an excess mortality of type 2 diabetic patients compared with the background population in all age groups. The excess mortality was most pronounced in men and in young patients.

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

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