The Danish investigation on iodine intake and thyroid disease (DanThyr): history and implications.

Due to mild-to-moderate iodine deficiency in Denmark, health authorities initiated a voluntary iodine fortification (IF) program in 1998, which became mandatory in 2000. In line with recommendations from the World Health Organization, the Danish investigation on iodine intake and thyroid disease (DanThyr) was established to monitor the effect on thyroid health and disease. The program involved different study designs and followed two Danish sub-populations in the years before IF and up till 20 years after. Results showed that the IF was successfully implemented and increased the level of iodine intake from mild-moderate iodine deficiency to low adequacy. The level of thyroglobulin and thyroid volume decreased following IF, and there was an indication of fewer thyroid nodules. The incidence of hyperthyroidism increased transiently following IF but subsequently decreased below the pre-fortification level. Conversely, thyroid-stimulating hormone levels and the prevalence of thyroid autoimmunity increased along with an increase in the incidence of hypothyroidism. These trends were mirrored in the trends in treatments for thyroid disease. Most differences in thyroid health and disease between regions with different iodine intake levels before IF attenuated. This review illustrates the importance of a monitoring program to detect both beneficial and adverse effects and exemplifies how a monitoring program can be conducted when a nationwide health promotion program - as IF - is initiated.

Physician-led medication reviews in polypharmacy patients treated with at least 12 medications in a type 2 diabetes outpatient clinic: A randomised trial.

AIMS: Medication reviews can be used to promote appropriate pharmacotherapy and negate the harmful consequences of polypharmacy. This study aimed to evaluate the effect of physician-led medication reviews and increased cross-sectoral communication as a supplement to standard care in a type 2 diabetes outpatient clinic. METHODS: This pragmatic randomised clinical trial enrolled patients with type 2 diabetes treated with at least 12 medications. The subjects were randomised to either standard care (standard care consultation at the outpatient clinic) or standard care plus a medication review consultation and increased cross-sectoral communication. The primary outcome was the number of medications used after six months. Health-related quality of life was quantified using the EuroQoL 5-dimension 5-level (EQ5D-5 L) questionnaire. RESULTS: We recruited 50 participants with a median age of 72 (IQR 67-75) years. The mean number of medications per patient changed from 17.9 to 14.3 in the intervention group and 17.6 to 17.2 in the control group (rate ratio 0.81). The reasons for discontinuations were medication no longer indicated (60%), safety issues (20%), efficacy issues (15%) or patient preferences (5%). There was a significant difference in the change in health-related quality of life (EQ5D-5 L index score) in favour of the intervention (0.111, 95% CI 0.001 to 0.221). CONCLUSIONS: Physician-led medication reviews and increased cross-sectoral communication in patients with type 2 diabetes treated with at least 12 medications reduced the number of medications used and improved health-related quality of life. Implementing and further investigating similar interventions as standard care seems reasonable.

Effects of 18-months metformin versus placebo in combination with three insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes: A post-hoc analysis of a randomized clinical trial.

Formation of reactive oxygen species has been linked to the development of diabetes complications. Treatment with metformin has been associated with a lower risk of developing diabetes complications, including when used in combination with insulin. Metformin inhibits Complex 1 in isolated mitochondria and thereby decreases the formation of reactive oxygen species. Thus, we post-hoc investigated the effect of metformin in combination with different insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes. Four hundred and fifteen individuals with type 2 diabetes were randomized (1:1) to blinded treatment with metformin (1,000 mg twice daily) versus placebo and to (1:1:1) open-label biphasic insulin, basal-bolus insulin, or basal insulin therapy in a 2 × 3 factorial design. RNA and DNA oxidation were determined at baseline and after 18 months measured as urinary excretions of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), respectively. Urinary excretion of 8-oxoGuo changed by +7.1% (95% CI: 0.5% to 14.0%, P = 0.03) following metformin versus placebo, whereas changes in 8-oxodG were comparable between intervention groups. Biphasic insulin decreased urinary excretion of 8-oxoGuo (within-group: -9.6% (95% CI: -14.4% to -4.4%)) more than basal-bolus insulin (within-group: 5.2% (95% CI: -0.5% to 11.2%)), P = 0.0002 between groups, and basal insulin (within-group: 3.7% (95% CI: -2.0% to 9.7%)), P = 0.0007 between groups. Urinary excretion of 8-oxodG decreased more in the biphasic insulin group (within-group: -9.9% (95% CI: -14.4% to -5.2%)) than basal-bolus insulin (within group effect: -1.2% (95% CI: -6.1% to 3.9%)), P = 0.01 between groups, whereas no difference was observed compared with basal insulin. In conclusion, eighteen months of metformin treatment in addition to different insulin regimens increased RNA oxidation, but not DNA oxidation. Biphasic insulin decreased both RNA and DNA oxidation compared with other insulin regimens.

Adjusting health care: practicing care for socially vulnerable type 2 diabetes patients.

BACKGROUND: Type 2 diabetes cluster in lower social groups and people with type 2 diabetes from lower social groups experience more complications, benefit less from health services and live shorter lives than people with type 2 diabetes from higher social groups. Different logics govern diabetes care and potentially influence the possibility of socially vulnerable type 2 diabetes patients to access and benefit from health services. In order to understand which practice and underlying logic enable socially vulnerable type 2 diabetes patients to access and benefit from diabetes care we aim to describe what professionals at a specialized diabetes clinic do to adjust services to patient's needs and make the tasks involved in diabetes care doable for socially vulnerable patients and how this work is embedded in an organizational and moral context. METHODS: Ethnographic fieldwork combining participant observation and interviews was carried out between February 2017 and March 2018 in a specialized diabetes clinic located in a socially deprived area in the capital region of Denmark. Sixteen patients (9 male, 7 female, aged 35-73 years) and 12 professionals (7 doctors, 4 nurses, 1 secretary) participated in the study. We used Annemarie Mol's concept of "the logic of care" to guide our analysis. RESULTS: Our analysis shows that the logic of care and the care practices in this clinic are characterized by a needs-based approach to treatment involving adjustment of services (permeability, timing, and content) and seeing the patient as a person with many needs. Throughout our description of selected care practices, we both characterize how health professionals practice this particular logic of care and the organizational and normative conditions that this logic is entangled with. CONCLUSIONS: Practicing diabetes care based on patients' needs involves individualization, something often described as an element of patient centred care. Our study shows that this ideal of individualization and adjustment of treatment is possible in practice. Organizational flexibility and an organizational culture that values patient needs enable needs-based care. In order for socially vulnerable type 2 diabetes patients to benefit from health services it is necessary to create conditions under which professionals can attend to these patients' multiple and complex needs. Adjusting care to these needs demand a variety of professional efforts some of which are hardly predictable or standardisable.

Perceived Benefits, Barriers, and Facilitators of a Digital Patient-Reported Outcomes Tool for Routine Diabetes Care: Protocol for a National, Multicenter, Mixed Methods Implementation Study.

BACKGROUND: There is growing evidence that digital patient-reported outcome (PRO) questionnaires and PRO-based decision support tools may help improve the active engagement of people with diabetes in self-care, thereby improving the quality of care. However, many barriers still exist for the real-world effectiveness and implementation of such PRO tools in routine care. Furthermore, limited research has evaluated the acceptability, feasibility, and benefits of such tools across different health care settings. OBJECTIVE: This study aims to evaluate the acceptability, feasibility, and perceived benefits of the Danish digital PRO diabetes tool in different health care settings in Denmark and to determine the factors affecting its implementation. Furthermore, the study evaluates the psychometric characteristics of the Danish PRO Diabetes Questionnaire and the validity of the scoring algorithms for dialogue support. The objective of this study is to guide the ongoing optimization of the PRO diabetes tool, its implementation, and the design of future randomized controlled effectiveness studies. METHODS: We designed a multicenter, mixed methods, single-arm acceptability-feasibility implementation study protocol to contribute to the real-world pilot test of a new digital PRO diabetes tool in routine diabetes care. The use of the tool involves two main steps. First, the people with diabetes will complete a digital PRO Diabetes Questionnaire in the days before a routine diabetes visit. Second, the health care professional (HCP) will use a digital PRO tool to review the PRO results together with the people with diabetes during the visit. The PRO diabetes tool is designed to encourage and support people to take an active role for the people with diabetes in their own care and to expedite the delivery of person-centered, collaborative, and coordinated care. RESULTS: A multicenter pilot study protocol and psychometrically designed digital data collection tools for evaluation were developed and deployed as part of a national evaluation of a new digital PRO diabetes intervention. A total of 598 people with diabetes and 34 HCPs completed the study protocol by April 1, 2021. CONCLUSIONS: A large-scale, mixed methods, multicenter study for evaluating the use of the nationally developed PRO Diabetes Questionnaire in routine care across all health care sectors in Denmark by using the RE-AIM (Reach, Efficacy, Adoption, Implementation and Maintenance) model as a framework has been designed and is ongoing. This study is expected to provide new important and detailed information about the real-world acceptability, perceived relevance, and benefits of the PRO diabetes tool among a large heterogeneous population of people with diabetes in Denmark and HCPs in different care settings. The results will be used to further improve the PRO tool, design implementation facilitation support strategies, and design future controlled effectiveness studies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/28391.

Does Subclinical Hypothyroidism Add Any Symptoms? Evidence from a Danish Population-Based Study.

BACKGROUND: Few studies have scrutinized the spectrum of symptoms in subclinical hypothyroidism. METHODS: From 3 Danish Investigation on Iodine Intake and Thyroid Diseases (DanThyr) cross-sectional surveys performed in the period 1997 to 2005, a total of 8903 subjects participated in a comprehensive investigation including blood samples and questionnaires on previous diseases, smoking habits, alcohol intake, and education. From the 3 surveys we included patients with subclinical hypothyroidism (n = 376) and euthyroid controls (n = 7619). We explored to what extent patients with subclinical hypothyroidism reported 13 previously identified hypothyroidism-associated symptoms (tiredness, dry skin, mood lability, constipation, palpitations, restlessness, shortness of breath, wheezing, globus sensation, difficulty swallowing, hair loss, dizziness/vertigo, and anterior neck pain). In various uni- and multivariate regression models we searched for circumstances predicting why some patients have more complaints than others. RESULTS: Subclinically hypothyroid patients did not report higher hypothyroidism score [(median, interquartile range), 2 (0-4) vs 2 (0-4), P = .25] compared with euthyroid controls. Within the group of subclinical hypothyroid patients, comorbidity had the highest impact on symptoms (tiredness, shortness of breath, wheezing; all P < .001); TSH level had no impact on symptom score; and younger age was accompanied by higher mental burden (tiredness, P < .001; mood lability, P < .001; restlessness, P = .012), whereas shortness of breath was associated with high body mass index (P < .001) and smoking (P = .007). CONCLUSION: Patients with a thyroid function test suggesting subclinical hypothyroidism do not experience thyroid disease-related symptoms more often than euthyroid subjects. In subclinical hypothyroidism, clinicians should focus on concomitant diseases rather than expecting symptomatic relief following levothyroxine substitution.

Efficacy of Bolus Calculation and Advanced Carbohydrate Counting in Type 2 Diabetes: A Randomized Clinical Trial.

Background: Carbohydrate counting and use of automated bolus calculators (ABCs) can help reduce HbA1c in type 1 diabetes but only limited evidence exists in type 2 diabetes. We evaluated the efficacy of advanced carbohydrate counting (ACC) and use of an ABC compared with manual insulin bolus calculation (MC) in persons with type 2 diabetes. Materials and Methods: A 24-week open-label, randomized clinical study was conducted in 79 persons with type 2 diabetes treated with basal-bolus insulin (mean age 62.5 ± 9.6 years, HbA1c 8.7% ± 1.0% [72 ± 11 mmol/mol], diabetes duration 18.7 ± 7.6 years). Participants were randomized 1:1 into two groups: ABC group received training in ACC and use of an ABC; MC group received training in ACC and manual calculation of insulin bolus. Participants wore blinded continuous glucose monitors for 6 days at baseline and at study end. Primary endpoint was change in HbA1c. Results: After 24 weeks, HbA1c decreased 0.8% (8.8 mmol/mol) in ABC group and 0.8% (9.0 mmol/mol) in MC group with no between-group difference (P = 0.96) and without increase in time in hypoglycemic range (sensor glucose <3.9 mmol/L). Glycemic variability decreased significantly in both groups, whereas the total insulin dose and body mass index (BMI) remained unchanged during the study. Treatment satisfaction increased significantly in both groups after 24 weeks. Conclusion: ACC is an effective, low-cost tool to reduce HbA1c and glycemic variability in persons with basal-bolus insulin-treated type 2 diabetes without increase in hypoglycemia or BMI. Similar effects were seen with use of an ABC and with use of manual bolus calculation. Trial registration: ClinicalTrials.gov NCT02887898.

Effect of Metformin vs. Placebo in Combination with Insulin Analogues on Bone Markers P1NP and CTX in Patients with Type 2 Diabetes Mellitus.

Preclinical studies have shown a potential osteoanabolic effect of metformin but human studies of how metformin affects bone turnover are few. A post hoc sub-study analysis of an 18-month multicenter, placebo-controlled, double-blinded trial in type 2 diabetes mellitus (T2DM), randomizing participants to metformin versus placebo both in combination with different insulin analogue regimens (Metformin + Insulin vs. Placebo + Insulin). Patients were not treatment naive at baseline, 83% had received metformin, 69% had received insulin, 57.5% had received the combination of metformin and insulin before entering the study. Bone formation and resorption were assessed by measuring, N-terminal propeptide of type I procollagen (P1NP) and C-terminal telopeptide of type I collagen (CTX) at baseline and end of study. The influence of gender, age, smoking, body mass index (BMI), T2DM duration, glycosylated hemoglobin A1c (HbA1c), c-reactive protein (CRP) and insulin dosage was also included in the analyses. The levels of bone formation marker P1NP and bone resorption marker CTX increased significantly in both groups during the trial. P1NP increased less in the Metformin + Insulin compared to the placebo + insulin group (p = 0.001) (between group difference change), while the increases in CTX levels (p = 0.11) were not different. CRP was inversely associated (p = 0.012) and insulin dosage (p = 0.011) was positively related with change in P1NP levels. BMI (p = 0.002) and HbA1C (p = 0.037) were inversely associated with change in CTX levels. During 18 months of treatment with metformin or placebo, both in combination with insulin, bone turnover increased in both groups. But the pattern was different as the bone formation marker (P1NP) increased less during Metformin + Insulin treatment, while change in bone resorption (CTX) was not significantly different between the two groups.

Changes in subtypes of overt thyrotoxicosis and hypothyroidism following iodine fortification.

OBJECTIVE: To investigate the impact of mandatory iodine fortification (IF) on the incidence of nosological subtypes of overt thyrotoxicosis and hypothyroidism. DESIGN: We identified and scrutinized all possible new cases of overt thyrotoxicosis and hypothyroidism in an open cohort in Northern Jutland (n = 309 434; 1 January 1997) during the years 2014-2016. Individual medical history was evaluated to verify and detail the incidence of overt thyroid dysfunction and for classification into nosological subtypes. A number of cases were excluded during final verification due to spontaneous normalization of thyroid function, as they had no medical history suggesting a known condition, which could transiently affect thyroid function (subacute/silent thyroiditis, PPTD and iatrogenic thyroid dysfunction). An identical survey was conducted in 1997-2000 prior to mandatory IF of salt (13 µg/g) that was in effect from year 2001. RESULTS: The standardized incidence rate (SIR) of verified overt thyrotoxicosis decreased markedly from 97.5/100 000/year in 1997-2000 to 48.8 in 2014-2016 (SIRR: 0.50 [95% CI: 0.45-0.56]). This was due to a distinct decrease in the SIR of multinodular toxic goitre (SIRR: 0.18 [0.15-0.23]), solitary toxic adenoma (SIRR: 0.26 [0.16-0.43]) and to a lesser degree Graves' disease (SIRR: 0.67 [0.56-0.79]). SIR for overt hypothyroidism was unaltered by 2014-2016 (SIRR: 1.03 [0.87-1.22]). However, age distribution shifted with more young and fewer elderly cases of verified overt hypothyroidism. CONCLUSION: Mandatory IF caused a substantial reduction in SIR of verified overt thyrotoxicosis (especially of nodular origin) while avoiding an increase in SIR of verified overt hypothyroidism.

Increased Incidence Rate of Hypothyroidism After Iodine Fortification in Denmark: A 20-Year Prospective Population-Based Study.

OBJECTIVE: To monitor the impact of a cautious iodine fortification (IF) on the incidence of overt hypothyroidism in two subpopulations with different levels of preexisting iodine deficiency (ID). DESIGN: A 20-year (1997 to 2016) prospective population-based study identified all new cases of diagnosed overt biochemical hypothyroidism in two open cohorts: a western cohort with moderate ID (n = 309,434; 1 January 1997) and an eastern cohort with mild ID (n = 224,535; 1 January 1997). A diagnostic algorithm was applied to all thyroid function tests performed within the study areas, and possible new cases were verified individually. Mandatory IF of salt was initiated in mid-2000 (13 ppm). The current study is a part of the DanThyr study. RESULTS: At baseline, standardized incidence rates (SIRs) of hypothyroidism were 32.9 and 47.3/100.000/y in the cohorts with moderate and mild ID, respectively. The SIR of hypothyroidism increased significantly in both cohorts after implementing mandatory IF, with peak values of 150% in 2014 to 2016 for the moderate ID cohort and 130% in 2004 to 2005 for the mild ID cohort. Significant increases in SIR were seen among the young and middle-aged participants of both cohorts, whereas no changes were seen among the elderly participants (≥60 years). The follow-up period for the mildly iodine-deficient cohort was restricted up to and including 2008. CONCLUSION: The cautious initiation of the IF program in Denmark caused a sustained increase in hypothyroidism incidence among subjects residing in areas of moderate and mild ID but only among the young and middle-aged participants.

Polypharmacy and medication deprescribing: A survey among multimorbid older adults in Denmark.

Polypharmacy is common among multimorbid adults and associated with increased morbidity and mortality. Excessive polypharmacy (ie, ≥10 medicine) is strongly associated with inappropriate medication use, but little is known about attitudes toward deprescribing in patients with excessive polypharmacy. We surveyed 100 Danish individuals aged 65 years and above with ≥10 prescribed medications, using the validated Patients' Attitudes Towards Deprescribing (PATD) instrument. Most participants (81, 81%) thought they took a large number of medications, and 79 (79%) believed that their medications were necessary. Even so, 85 (85%) reported that they would be willing to stop taking one or more of their regular medications if their doctor told them they could, and 11 (11%) felt that they took at least one regular medication that they no longer needed. When presented with visual presentation of various amounts of tablets and capsules, 62 (62%) of participants reported that they would be comfortable taking fewer medications than they did. Forty-two (42%) participants had experience with stopping a regular medication. Almost all participants (92%) wanted to receive follow-up by various means if a medication was discontinued. Forty-one (41%) participants were interested in a consultation at an outpatient clinic specializing in polypharmacy. Overall, the answers to the PATD questionnaire suggest that our cohort of Danish, multimorbid outpatients with extensive polypharmacy have a high confidence in their healthcare providers for medication-related decisions, even though some feel that they are taking more medications than they would like to and feel that some medications may be unnecessary. Our results underline the need for healthcare providers to offer medication reviews in patients with multimorbidity.

Thyrotoxicosis after iodine fortification. A 21-year Danish population-based study.

OBJECTIVE: Monitoring the influence of cautious iodine fortification (IF) on the incidence rate of overt thyrotoxicosis in Denmark with formerly frequent multinodular toxic goitre. DESIGN: A 21-year (1997-2017) prospective population-based study identified all new cases of overt biochemical thyrotoxicosis in two open cohorts: a Western cohort with moderate iodine deficiency (ID) and an Eastern cohort with mild ID (total n = 533 969 by 1 January 1997). A diagnostic algorithm was applied to all thyroid function tests performed within the study areas. Mandatory IF of salt was initiated in mid-2000 (13 ppm). This study is a part of DanThyr. RESULTS: The standardized incidence rate (SIR) of thyrotoxicosis at baseline (1997-1998) was 128.5/100.000/year in the cohort with moderate ID and 80.1 in the cohort with mild ID. SIR increased markedly in both cohorts during the initial years of IF (moderate/mild ID: +39/+52% in 2000-2001/2004-2005) and subsequently decreased to baseline level (mild ID) or below (moderate ID) by 2008. The decline was due to a marked decrease in the incidence rate among elderly subjects and a moderate decrease among the middle aged. The follow-up period for the mildly iodine deficient cohort was restricted to 2008. A continuous decline in SIR was observed for the remainder of the study period in the area with moderate ID (33% below baseline in 2016-2017). CONCLUSION: The rise in thyrotoxicosis incidence with cautious mandatory IF returned to baseline level after 7-8 years and levelled out at 33% below baseline in the population with previously moderate ID after 16-17 years.

Effect of Insulin Analogs on Frequency of Non-Severe Hypoglycemia in Patients with Type 1 Diabetes Prone to Severe Hypoglycemia: Much Higher Rates Detected by Continuous Glucose Monitoring than by Self-Monitoring of Blood Glucose-The HypoAna Trial.

BACKGROUND: Hypoglycemia is an increasingly important endpoint in clinical diabetes trials. The assessment of hypoglycemia should therefore be as complete as possible. Blinded continuous glucose monitoring (CGM) provides an improved opportunity to capture asymptomatic and nocturnal events. Here we report results from the HypoAna trial comparing all-analog-insulin therapy (aspart/detemir) with all-human-insulin therapy (neutral protamine Hagedorn/regular) on non-severe hypoglycemia (symptomatic and asymptomatic hypoglycemia) as assessed by blinded CGM and compared with data obtained by self-monitoring of blood glucose (SMBG) in patients with type 1 diabetes and recurrent severe hypoglycemia. METHODS: Fifty-three patients completed a substudy of 4 × 3 days of blinded CGM. CGM traces were reviewed for hypoglycemic events lasting 15 min or longer. RESULTS: At the threshold ≤3.9 mmol/L, the per-protocol analysis demonstrated a 40% rate reduction (95% confidence interval [CI] 20%-60%; P = 0.002) in nocturnal non-severe hypoglycemia during analog treatment, mainly due to a 40% rate reduction (95% CI 0%-70%; P = 0.03) of nocturnal asymptomatic hypoglycemia. Similar nonsignificant trends were seen at the glucose threshold ≤3.0 mmol/L. Overall CGM-detected that nocturnal asymptomatic hypoglycemia ≤3.9 mmol/L was ∼17 times more frequent than SMBG-detected episodes (52 vs. 3 events/patient-year). This translates into a time needed to treat one patient with insulin analogs to prevent one episode that is 34 times shorter using CGM data than SMBG data (1.4 vs. 47 weeks). CONCLUSIONS: Capturing hypoglycemic events by the conventional method of SMBG in patients with impaired awareness reveals only a limited number of events. Blinded CGM can provide more complete data, particularly in terms of asymptomatic and nocturnal events.

Video consultations as add-on to standard care among patients with type 2 diabetes not responding to standard regimens: a randomized controlled trial.

OBJECTIVE: To examine whether video consultations preceded by measurements of blood glucose, weight and blood pressure as add-on to standard care could contribute to achieving and maintaining good diabetes control among patients with poorly regulated type 2 diabetes (T2D). DESIGN: Randomized controlled trial. METHODS: 165 patients with T2D were randomized 1:1 to telemedicine intervention as add-on to clinic-based care or control (clinic-based care). The intervention consisted of monthly video conferences with a nurse via a tablet computer and lasted for 32 weeks. Regularly self-monitored measurements of blood sugar, blood pressure and weight were uploaded and visible to patient and nurse. Both groups were followed up six months after the end of the intervention period. PRIMARY ENDPOINT: HbA1c after eight months. RESULTS: Video conferences preceded by uploads of measurements as add-on to clinic-based care led to a significant reduction of HbA1c compared to that in standard care (0.69% vs 0.18%, P = 0.022). However, at six-month follow-up, the inter-group difference in HbA1c-reduction was no longer significant. Non-completers had higher HbA1c levels at baseline and a lower degree of education. CONCLUSION: Video consultations preceded by uploading relevant measurements can lead to clinically and statistically significant improvements in glycemic control among patients who have not responded to standard regimens. However, continuing effort and attention are essential as the effect does not persist when intervention ends. Furthermore, future studies should focus on differentiation as the most vulnerable patients are at greater risk of non-adherence.

The potential for improvement of outcomes by personalized insulin treatment of type 1 diabetes as assessed by analysis of single-patient data from a randomized controlled cross-over insulin trial.

AIMS: The evidence for optimal insulin treatment in type 1 diabetes is mainly based on randomised controlled trials applying a parallel-group design. Such trials yield robust general results but crucial individual treatment effects cannot be extracted. We aimed to assess the potential for further improvement of outcomes by personalized insulin therapy by analyzing data from a cross-over trial at individual level. METHODS: Post hoc analysis of data from a two-year multicentre, prospective, randomised, open, blinded endpoint (PROBE) trial (the HypoAna trial). In a cross-over design 114 patients with type 1 diabetes and recurrent severe hypoglycemia were treated with basal-bolus therapy based on analog (detemir/aspart) or human (NPH/regular) insulin aiming at maintenance of baseline HbA1c levels. For each patient a superior outcome was defined as fewer events of severe hypoglycemia defined by need for third party treatment assistance or a more than 0.4% (4.4mmol/mol) lower HbA1c. RESULTS: Only one quarter had comparable outcome of the two treatments in terms of rate of severe hypoglycemia or HbA1c. Twice as many patients had superior outcome of analog-based as compared to human insulin-based insulin treatment. The rate of severe hypoglycemia with the superior treatment was lower compared to the rates obtained with analog insulin and with human insulin (0.67, 1.09, and 1.57 episode per patient-year, respectively (p<0.0001)). CONCLUSIONS: Personalized insulin treatment of type 1 diabetes based on single-patient evidence may improve outcomes significantly compared to a general treatment approach.

Iodine deficiency in pregnancy is prevalent in vulnerable groups in Denmark.

INTRODUCTION: Iodine is essential for the production of thyroid hormones. In pregnancy, physiological changes occur that can lead to iodine deficiency and impairment of fetal neurological development. We aimed to assess the iodine intake in pregnant women in Eastern Denmark, compare iodine levels in Eastern and Western Denmark and to identify potentially vulnerable groups. METHODS: This was a cross-sectional cohort study of pregnant Danish women (n = 240). Questionnaires and urine samples were collected at the Ultrasound Clinic, Hvidovre Hospital, Denmark, and urinary iodine concentrations (UIC) (µg/l) were measured. Predictors of iodine supplement use were examined by multivariate logistic regression models. RESULTS: The pregnant women from Eastern Denmark had a median age of 30 years and the median gestational week at which they were included in the study was week 19. The majority took iodine-containing supplements (86%). The median UIC was 118 (interquartile range (IQR): 79-196) µg/l in iodine supplement users and 82 (IQR: 41-122) µg/l in non-users (p < 0.001). Predictors of not using iodine supplement in Eastern and Western Denmark were short maternal education, non-Danish origin and pre-pregnancy obesity. CONCLUSIONS: The iodine status in Danish pregnant women was below WHO recommendations. Iodine supplement non-users are at a particular risk of iodine deficiency. Low maternal education, non-Danish origin and pre-pregnancy obesity are predictors of non-iodine supplement use. An increase in iodine fortification may be recommended to improve the iodine status in pregnant Danish women. FUNDING: none. TRIAL REGISTRATION: not relevant.

Hypothyroid Symptoms Fail to Predict Thyroid Insufficiency in Old People: A Population-Based Case-Control Study.

BACKGROUND: Clinic-based studies have indicated that older hypothyroid patients may present only few symptoms. METHODS: In this population-based study of hypothyroidism, we investigated how the power of symptom presence predicts overt hypothyroidism in both young and older subjects. We identified patients newly diagnosed with overt autoimmune hypothyroidism in a population (n = 140, median thyroid-stimulating hormone, 54.5; 95% confidence interval [CI], 28.3-94.8; median total T4, 37; 95% CI, 18-52) and individually matched each patient with 4 controls free of thyroid disease (n = 560). Participants filled out questionnaires concerning the presence and duration of symptoms. We compared the usefulness of hypothyroidism-associated symptoms in predicting overt hypothyroidism in different age groups (young: <50 years, middle age: 50-59 years, old: ≥60 years) also taking various confounders into account. RESULTS: In young hypothyroid patients, all 13 hypothyroidism-associated symptoms studied were more prevalent than in their matched controls, whereas only 3 of those (tiredness, shortness of breath, and wheezing) were more prevalent in old patients. The mean numbers of symptoms presented at disease onset were 6.2, 5.0, and 3.6 at the ages of 0 to 49 years, 50 to 59 years, and 60+ years, respectively. In young versus old people with 0 to 1 symptoms, the odds ratio for being hypothyroid was 0.04 (95% CI, 0.007-0.18) versus 0.34 (95% CI, 0.15-0.78) (reference all other groups). In young versus old subjects reporting ≥4 symptoms, the odds ratio for being hypothyroid was 16.4 (95% CI, 6.96-40.0) versus 2.22 (95% CI, 1.001-4.90). Receiver operating characteristic analyses revealed that the symptom score was an excellent tool for predicting hypothyroidism in young men (area under the receiver operating characteristic curve, 0.91; 95% CI, 0.82-0.998), whereas it was poor in evaluating older women (area under the receiver operating characteristic curve, 0.64; 95% CI, 0.54-0.75). CONCLUSION: Hypothyroid symptom score is a good discriminating tool to identify hypothyroidism in young patients but fails to identify hypothyroidism in the elderly. Thus, thyroid function should be tested on wide indications in old age.

Short-term cost-effectiveness of insulin detemir and insulin aspart in people with type 1 diabetes who are prone to recurrent severe hypoglycemia.

OBJECTIVE: Based on the data of the HypoAna trial (ClinicalTrials.gov NCT00346996), a short-term cost-effectiveness analysis was conducted comparing an all insulin analogue regimen with an all human insulin regimen in people with type 1 diabetes who are prone to recurrent severe hypoglycemia. METHODS: Clinical data from the HypoAna trial and Danish cost data related to the treatment of severe hypoglycemia were used to populate a 1-year cost-effectiveness analysis. Hypoglycemia quality-of-life data were based on previously published utility values, used to calculate the quality-adjusted life-years (QALYs) gained. Sensitivity analyses were conducted to test the robustness of the analysis. The main outcome measure was the incremental cost-effectiveness ratio (ICER). RESULTS: The insulin analogue regimen was associated with greater total costs compared with the human insulin regimen (20,418 DKK [1972 GBP] vs. 18,558 DKK [1793 GBP], respectively), primarily driven by the difference in insulin costs. Total costs for corrective actions for hypoglycemic events, however, were lower in the insulin analogue group (927 DKK [89 GBP]) compared with the human insulin group (1311 DKK [127 GBP]), primarily due to a lower event rate. QALYs were higher with insulin analogues vs. human insulin (difference 0.0672). The resulting ICER was 27,685 DKK (2674 GBP) per QALY gained, which is well below the generally accepted cost-effectiveness threshold. CONCLUSIONS: The analysis shows that treating people with type 1 diabetes who are prone to recurrent severe hypoglycemia with an insulin analogue regimen is cost-effective compared with a human insulin regimen.

Iodine excretion in school children in Copenhagen.

INTRODUCTION: Studies of dietary habits show a high iodine intake in children in Denmark. Iodine excretion in children has not previously been assessed. Iodine excretion in adults is below the recommended threshold, and it is therefore being discussed to increase the fortification level. The main objective of this study was to assess iodine excretion in children living in Copenhagen to establish whether a moderate increase in iodine fortification would lead to excess iodine intake in this group. METHODS: Children in first and fifth grade were recruited through schools in Copenhagen. In total, 244 children de-ivered a urine sample. Urine samples were analysed for iodine and creatinine, and the results were expressed as urinary iodine concentration (UIC) and as estimated 24-h iodine excretion. Iodine excretion in children was also compared with that of adults living in the same area, investigated in a prior study. RESULTS: The median UIC was within the recommended level; 145 (range: 116-201) µg/l for boys and 128 (range: 87-184) µg/l for girls, and was lower in fifth grade students than in first grade students. Estimated 24-h iodine excretion was higher in boys than in girls, but did not differ according to grade. The UIC was higher in children than in adults from the same area. CONCLUSIONS: The iodine excretion among schoolchildren in Copenhagen, an area with a relatively high iodine content in tap water, was within the recommended range as assessed by the UIC. An increased iodine fortification will not have negative consequences for this group. FUNDING: The Ministry of Food, Agriculture and Fisheries. TRIAL REGISTRATION: not relevant.

Serum thyroglobulin as a biomarker of iodine deficiency in adult populations.

OBJECTIVE: To clarify which factors may influence the serum Tg level in an adult population and how this may affect Tg as a biomarker of iodine deficiency (ID). DESIGN AND METHODS: Two identical cross-sectional studies were performed before (C1a: 1997-98, n = 4649) and after (C2: 2004-05, n = 3570) the Danish mandatory iodine fortification (IF) of salt (2000). Additionally, a follow-up study of C1a was performed after IF (C1b: 2008-10, n = 2465). The studies took place in two regions with mild (Copenhagen) and moderate (Aalborg) ID before IF. Serum Tg was measured by immunoradiometric method and investigated as outcome variable in multivariate models. RESULTS: Multiple factors were associated with serum Tg. Some were directly related to iodine intake (cohort, urinary iodine concentration (UIC) level and region), and some were likely mediators of iodine intake effects on Tg (thyroid nodularity, thyroid size and autonomy with low TSH). Others were caused by Tg assay interference (Tg-Ab positivity), aggravation of ID (childbirths and smoking) or TSH stimulation of the thyroid. Estimated 24-h urinary iodine excretion was a more sensitive predictor of Tg than UIC. Iodine supplement users had low median Tg values compared with nonusers both before and after IF. CONCLUSIONS: Multiple factors should be taken into consideration when evaluating Tg as a marker of ID in adult populations, and the Tg results may depend on the assay used. Still, Tg is a sensitive marker of ID. We suggest including a reference population with known sufficient iodine intake when Tg is used to evaluate ID.