A Randomized, Open-Label Comparison of Once-Weekly Insulin Icodec Titration Strategies Versus Once-Daily Insulin Glargine U100.

OBJECTIVE: Insulin icodec is a novel once-weekly basal insulin analog. This trial investigated the efficacy and safety of icodec using different once-weekly titration algorithms. RESEARCH DESIGN AND METHODS: This was a phase 2, randomized, open-label, 16-week, treat-to-target study. Insulin-naive adults (n = 205) with type 2 diabetes and HbA1c 7-10% while treated with oral glucose-lowering medications initiated once-weekly icodec titrations A (prebreakfast self-measured blood glucose target 80-130 mg/dL; adjustment ±21 units/week; n = 51), B (80-130 mg/dL; ±28 units/week; n = 51), or C (70-108 mg/dL; ±28 units/week; n = 52), or once-daily insulin glargine 100 units/mL (IGlar U100) (80-130 mg/dL; ±4 units/day; n = 51), all titrated weekly. Percentage of time in range (TIR) (70-180 mg/dL) during weeks 15 and 16 was measured using continuous glucose monitoring. RESULTS: TIR improved from baseline (means: A, 57.0%; B, 55.2%; C, 51.0%; IGlar U100, 55.3%) to weeks 15 and 16 (estimated mean: A, 76.6%; B, 83.0%; C, 80.9%; IGlar U100, 75.9%). TIR was greater for titration B than for IGlar U100 (estimated treatment difference 7.08%-points; 95% CI 2.12 to 12.04; P = 0.005). No unexpected safety signals were observed. Level 2 hypoglycemia (<54 mg/dL) was low in all groups (0.05, 0.15, 0.38, 0.00 events per patient-year of exposure for icodec titrations A, B, and C and IGlar U100, respectively), with no episodes of severe hypoglycemia. CONCLUSIONS: Once-weekly icodec was efficacious and well tolerated across all three titration algorithms investigated. The results for icodec titration A (80-130 mg/dL; ±21 units/week) displayed the best balance between glycemic control and risk of hypoglycemia.

Switching to Degludec is Associated with Reduced Hypoglycaemia, Irrespective of Definition Used or Patient Characteristics: Secondary Analysis of the ReFLeCT Prospective, Observational Study.

INTRODUCTION: Hypoglycaemia is a common side effect of insulin therapy; low or high glycated haemoglobin (HbA1c) levels, history of hypoglycaemia or long diabetes duration are known modifiers of hypoglycaemia risk. In randomised clinical trials, lower rates of hypoglycaemia have been observed with the new-generation insulin analogue, long-acting insulin degludec, compared with other basal insulins. METHODS: The ReFLeCT study was a prospective observational study over 12 months. Patient-reported diary data on hypoglycaemia were collected from patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) who were switching from other basal insulins to insulin degludec (degludec) at their physician's discretion in routine clinical care. Two secondary analyses were undertaken to investigate the change in number of hypoglycaemic events: a post hoc analysis using the updated American Diabetes Association (ADA) level 1, 2 and 3 hypoglycaemia definitions, and a pre-specified analysis using patient characteristics (baseline HbA1c, diabetes duration, and physician's rationale for initiating degludec). RESULTS: Switching to degludec was associated with significantly fewer hypoglycaemic events for all definitions in T1D, and level 1 and 2 in T2D (too few level 3 events for statistical comparison). Moreover, patient characteristics did not influence the observed reduction in hypoglycaemia in T1D and T2D. CONCLUSION: These results demonstrate that switching to degludec from other basal insulins was associated with reduced rates of hypoglycaemia, irrespective of the definition used or baseline patient characteristics. TRIAL REGISTRATION: NCT02392117.

Low blood sugar levels (hypoglycaemia) are a common, and sometimes serious, side effect of treatment with insulin in people with diabetes. In the ReFleCT study, adults with type 1 (T1D) and type 2 diabetes (T2D) were asked to complete a diary for 12 months when their doctor changed their previous long-acting insulin treatment to insulin degludec (degludec). The key outcome of the study was whether the frequency of hypoglycaemia changed when a patient's insulin treatment was switched. Here, we used the diary information from the ReFLeCT study to investigate whether the change in the rate of hypoglycaemia was related to the way hypoglycaemia was defined, or to patients' characteristics at the time their insulin was switched. These characteristics included the length of time that patients had had diabetes, their blood sugar control, and their doctor's reason for changing their medication. Our findings showed that the way hypoglycaemia was defined, and patients' characteristics, did not generally influence the frequency of hypoglycaemia for patients with T1D or T2D. However, the most severe hypoglycaemia in patients with T2D occurred too infrequently to be assessed. Patients in all groups had less hypoglycaemia overall after switching compared with their previous treatment, suggesting that degludec may be a treatment option for a broad range of patients with diabetes.

Switching to Degludec From Other Basal Insulins Is Associated With Reduced Hypoglycemia Rates: A Prospective Study.

CONTEXT: Observational studies of insulin degludec (degludec) with hypoglycemia events prospectively recorded are lacking. OBJECTIVE: To evaluate the safety and effectiveness of degludec in patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) switching from other basal insulins in routine care. DESIGN: Results From Real-World Clinical Treatment With Tresiba® was a multinational, multicenter, prospective, observational, single-arm study comprising a 4-week baseline period (preswitch basal insulin) and 12-month follow-up (degludec). SETTING: Routine clinical practice. PATIENTS OR OTHER PARTICIPANTS: Insulin-treated patients (≥18 years) with T1D (n = 556) or T2D (n = 611) with treatment plans to initiate degludec. INTERVENTIONS: Switching to degludec from other basal insulins. MAIN OUTCOME MEASURE: Change from baseline in number of overall hypoglycemic events recorded in patient diaries. RESULTS: In T1D, the 12-month follow-up/baseline rate ratios (95% CI) of overall [0.80 (0.74 to 0.88)], nonsevere [0.83 (0.76 to 0.91)], severe [0.28 (0.14 to 0.56)], and nocturnal [0.61 (0.50 to 0.73)] hypoglycemia suggested significantly lower hypoglycemia rates with degludec (all Ps < 0.001). At 12 months, HbA1c, fasting plasma glucose (FPG), and basal insulin dosage decreased significantly. Body weight increased, and treatment satisfaction improved significantly. In T2D, the hypoglycemia rate ratios were overall [0.46 (0.38 to 0.56)], nonsevere [0.53 (0.44 to 0.64)], and nocturnal [0.35 (0.20 to 0.62)] (all Ps < 0.001; too few events for analysis of severe hypoglycemia). At 12 months, HbA1c and FPG decreased significantly. Body weight and insulin dosages remained unchanged, and treatment satisfaction was significantly improved. CONCLUSIONS: In a routine clinical care setting, switching to degludec from other basal insulins was associated with significantly lower rates of hypoglycemia, improved glycemic control, and treatment satisfaction in patients with T1D or T2D.

Historical Study (1986-2014): Improvements in Nutritional Status of Dialysis Patients.

OBJECTIVE: Malnutrition is common in dialysis patients and is associated with adverse clinical outcomes. Despite an increased focus on improved nutrition in dialysis patients, it is claimed that the prevalence of malnutrition in this group of patients has not changed during the last decades. Direct historical comparisons of the nutritional status of dialysis patients have never been published. To directly compare the nutritional status of past and current dialysis patients, we implemented the methodology of a study from 1986 on a population of dialysis patients in 2014. DESIGN: Historical study comparing results of two cross-sectional studies performed in 1986 and 2014. SETTING: We compared the nutritional status of hemodialysis (HD) and peritoneal dialysis (PD) patients attending the dialysis center at Roskilde Hospital, Denmark, in February to June 2014, with that of HD and PD patients treated at the dialysis center at Fredericia Hospital, Denmark, in April 1986. SUBJECTS: Maintenance PD and HD patients (n = 64 in 2014 and n = 48 in 1986). METHODS: We performed anthropometry (body weight, triceps skinfold, and midarm muscle circumferences [MAMCs]) and determined plasma transferrin. MAIN OUTCOME MEASURE: Relative body weight, triceps skinfold, MAMC, body mass index, and prevalence of protein-caloric malnutrition as defined in the original study from 1986. RESULTS: Average relative body weight, triceps skinfold, MAMC, and body mass index were significantly higher in 2014 compared with 1986. The prevalence of protein-caloric malnutrition was significantly lower in 2014 (18%) compared with 1986 (52%). CONCLUSIONS: The nutritional status of maintenance dialysis patients has improved during the last 3 decades. The reason for this improvement could not be identified in the present study, but the most likely contributors are the higher prevalence of obesity in the general population, less predialytic malnutrition, and an improved focus on nutrition in maintenance dialysis patients.

Nutritional Status of Maintenance Dialysis Patients: Low Lean Body Mass Index and Obesity Are Common, Protein-Energy Wasting Is Uncommon.

BACKGROUND AND AIMS: Maintenance dialysis patients are at increased risk of abnormal nutritional status due to numerous causative factors, both nutritional and non-nutritional. The present study assessed the current prevalence of protein-energy wasting, low lean body mass index and obesity in maintenance dialysis patients, and compared different methods of nutritional assessment. METHODS: In a cross-sectional study conducted in 2014 at Roskilde Hospital, Denmark, we performed anthropometry (body weight, skinfolds, mid-arm, waist, and hip circumferences), and determined plasma albumin and normalized protein catabolic rate in order to assess the prevalence of protein-energy wasting, low lean body mass index and obesity in these patients. RESULTS: Seventy-nine eligible maintenance dialysis patients participated. The prevalence of protein-energy wasted patients was 4% (95% CI: 2-12) as assessed by the coexistence of low lean body mass index and low fat mass index. Low lean body mass index was seen in 32% (95% CI: 22-44). Obesity prevalence as assessed from fat mass index was 43% (95% CI: 32-55). Coexistence of low lean body mass index and obesity was seen in 10% (95% CI: 5-19). The prevalence of protein-energy wasting and obesity varied considerably, depending on nutritional assessment methodology. CONCLUSIONS: Our data indicate that protein-energy wasting is uncommon, whereas low lean body mass index and obesity are frequent conditions among patients in maintenance dialysis. A focus on how to increase and preserve lean body mass in dialysis patients is suggested in the future. In order to clearly distinguish between shortage, sufficiency and abundance of protein and/or fat deposits in maintenance dialysis patients, we suggest the simple measurements of lean body mass index and fat mass index.

Spirometry utilisation among Danish adults initiating medication targeting obstructive lung disease.

UNLABELLED: This PhD thesis was written during my employment at the Research Unit of General Practice in Odense, University of Southern Denmark. It comprises an overview and three papers, all published or submitted for publication in international peer-reviewed scientific journals.   BACKGROUND: Non-infectious dyspnoea, chronic cough and wheezing are common symptoms in the population. Patients often present with these symptoms in general practice and have a high probability of having obstructive lung diseases. However, there is an indication that the majority of these patients are treated empirically with pharmacotherapy targeting obstructive lung disease and only few have additional tests conducted, although the predictive value of respiratory symptoms for diagnosing obstructive lung disease has proven to be low. Spirometry is recommended as the gold standard for confirming obstructive lung disease, and testing can also rule out airway obstruction in patients with respiratory symptoms caused by other illnesses, such as heart failure or lung cancer. Initiating medication for obstructive lung disease without spirometry entails the risk of these patients experiencing unnecessary delay in the diagnostic process and being exposed to unnecessary economic costs and medication risks. The literature has indicated that many users of medication targeting obstructive lung medication have not had spirometry performed and do not actually have obstructive lung disease. This potential quality gap needs to be assessed. Also, in order to target interventions enhancing earlier spirometry utilisation among patients initiating medication targeting obstructive lung disease, improved knowledge on patient and practice factors associated with spirometry testing is needed.   AIMS: Among first time users of obstructive lung medication we aimed: - To assess to what extent spirometry was performed within the first year of medication use (Study I) - To assess if patient characteristics like socioeconomic and demographic status were associated with spirometry testing (Studies I &II) - To assess if general practice characteristics were associated with spirometry testing (Study III)   METHODS: Register-based observational studies on first time users of medication targeting obstructive lung disease among adults over 18 years of age in 2008. The patient cohort was identified in the Danish National Prescription Register where all redeemed prescriptions for medication targeting obstructive lung disease are registered. All spirometry tests provided to the patient cohort in the time period 2007-2010 were extracted from the Danish National Health Service Register and the Danish National Patient Register and we assessed if patients had a spirometry registered in an 18- month time period counting from 6 months before to 12 months after their first redemption of medication. We linked socioeconomic and demographic patient variables and variables on practice characteristics from National registers to assess their association with patients having spirometry performed.   RESULTS: A total of 40,969 adults initiated medication targeting obstructive lung medication in 2008 in Denmark. The mean age of the cohort was 55.6 years (SD18.7) and approximately half of the mediations users had spirometry test performed. Initiating several types of medication targeting obstructive lung disease within the first year and redeeming medication repeatedly increased the odds of having spirometry performed. Women and patients in the oldest age categories had reduced odds of having spirometry performed. Being unemployed reduced the odds for spirometry testing among adults less than 65 years of age. Also, among the elderly (>65 years) living alone reduced the odds for spirometry testing; however this was only statistically significant among men. Some practice characteristics also influenced the odds for spirometry testing. Patients in partnership practices had higher odds for spirometry testing. Among singlehanded practices higher odds for spirometry testing was seen if practice had training practice status. We saw decreasing odds for spirometry testing with increasing age among doctors.   CONCLUSION AND PERSPECTIVES: This study has shown a lack of spirometry testing among patients initiating medication targeting obstructive lung disease. This underuse of spirometry testing indicates a quality gap and increased focus of spirometry utilization is needed when patients initiate medication targeting obstructive lung disease. The variation reported in spirometry testing across patient and practice characteristics was most predominant with regard to increasing age among patients and doctors, the remaining variables only account for small variations. However identification of these variations can help guide general practitioners to identify patients at increased risk of not having spirometry performed and help target future interventions for primary care.

Does switching from oral to subcutaneous administration of methotrexate influence on patient reported gastro-intestinal adverse effects?

INTRODUCTION: When treating patients with methotrexate (MTX) the most frequently reported adverse effects (AE) are gastrointestinal (GI) with nausea being reported by 10-20%. If intolerable AE of oral MTX persist, switching from oral to subcutaneous (SC) or intramuscular (IM) administration is common. However, this approach is largely empirical and the evidence is inconsistent. To our knowledge, this will be the first study to estimate the change in GI AE of switching from oral to SC MTX. METHODS: A retrospective postal survey was sent to patients who had changed from oral MTX to SC MTX. GI AE was rated by visual analogue scale (VAS) regarding frequency and intensity of nausea, frequency of vomiting and frequency of discomfort. All participants gave informed consent. No further ethical clearance was necessary according to national law. RESULTS: Of the sample 39/57 (68.4%) responded. Significant reductions in VAS were found in three of four primary outcome measures for GI AE. Only frequency of vomiting was not significantly reduced. CONCLUSION: Our findings support the common practice of switching from oral to SC MTX to alleviate GI AE, however, additional research is needed in order to clarify this rarely studied subject.

General practice variation in spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease in Denmark: a population-based observational study.

BACKGROUND: Spirometry testing is essential to confirm an obstructive lung disease, but studies have reported that a large proportion of patients diagnosed with COPD or asthma have no history of spirometry testing. Also, it has been shown that many patients are prescribed medication for obstructive lung disease without a relevant diagnosis or spirometry test registered. General practice characteristics have been reported to influence diagnosis and management of several chronic diseases. However, these findings are inconsistent, and it is uncertain whether practice characteristics influence spirometry testing among patients receiving medication for obstructive lung disease. The aim of this study was therefore to examine if practice characteristics are associated with spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease. METHODS: A national register-based cohort study was performed. All patients over 18 years receiving first-time prescriptions for medication targeting obstructive lung disease in 2008 were identified and detailed patient-specific data on sociodemographic status and spirometry tests were extracted. Information on practice characteristics like number of doctors, number of patients per doctor, training practice status, as well as age and gender of the general practitioners was linked to each medication user. RESULTS: Partnership practices had a higher odds ratio (OR) of performing spirometry compared with single-handed practices (OR 1.24, CI 1.09-1.40). We found a significant association between increasing general practitioner age and decreasing spirometry testing. This tendency was most pronounced among partnership practices, where doctors over 65 years had the lowest odds of spirometry testing (OR 0.25, CI 0.10-0.61). Training practice status was significantly associated with spirometry testing among single-handed practices (OR 1.40, CI 1.10-1.79). CONCLUSION: Some of the variation in spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease was associated with practice characteristics. This variation in performance may indicate a potential for quality improvement.

Influence of socioeconomic and demographic status on spirometry testing in patients initiating medication targeting obstructive lung disease: a population-based cohort study.

BACKGROUND: Socioeconomic status is known to influence the prevalence, severity and mortality of obstructive lung diseases, but it is uncertain whether it affects the use of diagnostic spirometry in patients initiating treatment for these conditions. The objective of this paper was to examine a possible association between education, income, labour market affiliation, cohabitation status and having spirometry performed when initiating medication targeting obstructive pulmonary disease. METHODS: We conducted a population-based cohort study. Danish national registers were linked, retrieving data on prescriptions, spirometry testing, socioeconomic and demographic variables in all first time users of medication targeting obstructive lung disease in 2008. RESULTS: A total of 37,734 persons were included and approximately half of the cohort had spirometry performed. Among medication users under 65 years of age, being unemployed was significantly associated with reduced odds of having spirometry performed, the strongest association was seen in men (OR = 0.82, CI = 0.73-0.91). Medium income was associated with increased odds of having spirometry performed in men (OR =1.18, CI = 1.06-1.30) and high educational level (>12 years) was associated with reduced odds of having spirometry performed in women (OR = 0.86, CI = 0.78-0.94). Cohabitation status was not associated with having spirometry performed. Among medication users over 65 years of age, living alone was associated with reduced odds of having spirometry performed among men (OR = 0.78, CI = 0.69-0.88). CONCLUSION: Social inequity in spirometry testing among patients initiating medication targeting obstructive lung disease was confirmed in this study. Increased focus on spirometry testing among elderly men living alone, among the unemployed and among women with higher education is required when initiating medication.

Lack of spirometry use in Danish patients initiating medication targeting obstructive lung disease.

BACKGROUND: Research indicates that a large proportion of patients using medication targeting obstructive lung disease have no history of spirometry testing. OBJECTIVE: To investigate the use of spirometry when initiating pulmonary medication targeting obstructive lung disease and to explore possible patient characteristics associated with undergoing spirometry. METHODS: Population-based cohort study. Three Danish National registers were linked enabling a retrieval of data on all primary and secondary healthcare services provided in the time period 2007-2010. RESULTS: In 2008 a total of 40,969 patients were registered as first time users of pulmonary medication targeting obstructive lung disease. The mean age of the study cohort was 55.6 yrs (SD 18.7). Spirometry test had been performed in 20,262 (49.5%) of the study cohort in the period from 6 months before to 12 months after their first prescription. Just above one third of the cohort, 14,275 (34.8%), had undergone spirometry in the two-month period close to redemption of their first prescription. Women and patients in the oldest age categories were less likely to have spirometry performed. CONCLUSIONS: Many patients initiate medication targeting obstructive pulmonary disease without having airway obstruction confirmed through spirometry. Only one third of the study cohort had a spirometry performed when initiating medication and half had still not undergone spirometry after a year. There should be an increased focus on confirming airway obstruction when initiating medication.

[Test of knowledge and skills enhances learning]. / Test af viden og færdigheder øger indlæring.

Test-enhanced learning is an evidence-based pedagogical tool for enhancing retention of both knowledge and skills. The phenomenon is independent of external factors such as feedback and intention to learn. The mechanism is complex and possibly related to stress and gender. Tests immediately after learning are most effective - and formats that support test-enhanced learning most effectively involve composing an answer or actively performing a skill. Use of tests in education should be integrated in the curriculum ensuring that the tests relevantly complement and enhance learning of knowledge or skills.

[Drug marketing: methods, effect and regulation]. / Markedsføring af laegemidler: metoder, effekt og regulering.

The interaction between pharmaceutical companies and physicians has been discussed intensely in recent years. Pharmaceutical companies use multiple marketing methods which are targeted at physicians: advertisement, visits by representatives, distribution of free drug samples or other gifts, sponsoring of meetings and seminars. It has been shown that this interaction influences physicians' prescriptions inappropriately. As the interaction is inevitable, it should be further addressed how this interaction may be regulated to minimize non-rational prescribing.

Biological effects of rAAV-caAlk2 coating on structural allograft healing.

Structural bone allografts often fracture due to their lack of osteogenic and remodeling potential. To overcome these limitations, we utilized allografts coated with recombinant adeno-associated virus (rAAV) that mediate in vivo gene transfer. Using beta-galactosidase as a reporter gene, we show that 4-mm murine femoral allografts coated with rAAV-LacZ are capable of transducing adjacent inflammatory cells and osteoblasts in the fracture callus following transplantation. While this LacZ vector had no effect on allograft healing, bone morphogenetic protein signals delivered via rAAV-caAlk2 coating induced endochondral bone formation directly on the cortical surface of the allograft by day 14. By day 28 there was evidence of remodeling of the new woven bone and massive osteoclastic resorption of the cortical surface of the rAAV-caAlk2-coated allografts only. Micro-CT analysis of rAAV-LacZ- vs rAAV-caAlk2-coated allografts after 42 days of healing demonstrated a significant increase in new bone formation (0.67 +/- 0.21 vs 2.49 +/- 0.40 mm(3); P < 0.005). Furthermore, the 3D micro-CT images of femurs grafted with rAAV-Alk2-coated allografts provided the first evidence that complete bridging of bone around a cortical allograft is possible. These results indicate that cell-free, rAAV-coated allografts have the potential to revitalize in vivo following transplantation.

Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy.

Structural allograft healing is limited because of a lack of vascularization and remodeling. To study this we developed a mouse model that recapitulates the clinical aspects of live autograft and processed allograft healing. Gene expression analyses showed that there is a substantial decrease in the genes encoding RANKL and VEGF during allograft healing. Loss-of-function studies showed that both factors are required for autograft healing. To determine whether addition of these signals could stimulate allograft vascularization and remodeling, we developed a new approach in which rAAV can be freeze-dried onto the cortical surface without losing infectivity. We show that combination rAAV-RANKL- and rAAV-VEGF-coated allografts show marked remodeling and vascularization, which leads to a new bone collar around the graft. In conclusion, we find that RANKL and VEGF are necessary and sufficient for efficient autograft remodeling and can be transferred using rAAV to revitalize structural allografts.