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Background and Aims: Nocturnal hypoglycemia is mainly a consequence of inappropriate basal insulin therapy in type 1 diabetes (T1D) and may compromise optimal glycemic control. Insulin degludec is associated with a lower risk of nocturnal hypoglycemia in T1D. As nocturnal hypoglycemia is often asymptomatic, we applied continuous glucose monitoring (CGM) to detect a more precise occurrence of nocturnal hypoglycemia in the HypoDeg trial, comparing insulin degludec with insulin glargine U100 in people with T1D and previous nocturnal severe hypoglycemia. Materials and Methods: In the HypoDeg trial, 149 people with T1D were included in an open-label randomized cross-over trial. Sixty-seven participants accepted optional participation in the predefined substudy of 4 × 6 days of blinded CGM requiring completion of at least one CGM period in each treatment arm. CGM data were reviewed for hypoglycemic events. Results: Treatment with insulin degludec resulted in a relative rate reduction (RRR) of 36% (95% confidence interval [CI]: 10%-54%; P

AimTo compare nocturnal glucose profiles according to hourly plasma glucose measurements during treatment with insulin degludec and insulin glargine U100 in a cohort of people with type 1 diabetes prone to nocturnal severe hypoglycaemia.Materials and methodsThe HypoDeg trial is a 2-year investigator-initiated, randomized, controlled crossover trial in 149 participants randomized to treatment with insulin degludec and insulin glargine U100 for 12 months each. The 51 participants in this predefined substudy stayed at least one night in hospital during each treatment arm for plasma glucose samples to be taken. Endpoints were glucose profiles, including mean plasma glucose, glycaemic variability and risk of hypoglycaemia.ResultsThere were no differences between treatments regarding mean plasma glucose. We saw a flatter glucose profile during insulin degludec compared with insulin glargine U100 treatment, which had a nadir at 4:00 AM, with a subsequent rise. During treatment with insulin degludec, the participants had lower glycaemic variability, with an estimated treatment difference of −4.3% (95% confidence interval [CI] −8.1 to −0.5; P ConclusionBased on nocturnal plasma glucose measurements, treatment with insulin degludec compared with insulin glargine U100 administered in the evening results in lower glycaemic variability and lower risk of nocturnal hypoglycaemia without differences in mean plasma glucose. Aim: To compare nocturnal glucose profiles according to hourly plasma glucose measurements during treatment with insulin degludec and insulin glargine U100 in a cohort of people with type 1 diabetes prone to nocturnal severe hypoglycaemia. Materials and methods: The HypoDeg trial is a 2-year investigator-initiated, randomized, controlled crossover trial in 149 participants randomized to treatment with insulin degludec and insulin glargine U100 for 12 months each. The 51 participants in this predefined substudy stayed at least one night in hospital during each treatment arm for plasma glucose samples to be taken. Endpoints were glucose profiles, including mean plasma glucose, glycaemic variability and risk of hypoglycaemia. Results: There were no differences between treatments regarding mean plasma glucose. We saw a flatter glucose profile during insulin degludec compared with insulin glargine U100 treatment, which had a nadir at 4:00 AM, with a subsequent rise. During treatment with insulin degludec, the participants had lower glycaemic variability, with an estimated treatment difference of −4.3% (95% confidence interval [CI] −8.1 to −0.5; P < 0.05). Participants treated with insulin degludec were less likely to experience nocturnal hypoglycaemia below 3.0 mmol/L (hazard ratio 0.36 [95% CI 0.17-0.73; P < 0.05]). Conclusion: Based on nocturnal plasma glucose measurements, treatment with insulin degludec compared with insulin glargine U100 administered in the evening results in lower glycaemic variability and lower risk of nocturnal hypoglycaemia without differences in mean plasma glucose.

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.

Aims/hypothesis Nocturnal hypoglycaemia remains a main limiting factor for achieving the recommended glycaemic target in type 1 diabetes (T1D). The long-acting insulin analogue degludec reduces the risk of nocturnal hypoglycaemia in patients with T1D at low risk of such events. This study investigates whether insulin degludec compared with insulin glargine U100 reduces the risk of nocturnal and severe hypoglycaemia in patients prone to nocturnal severe hypoglycaemia. Methods Adults with T1D and at least one episode of nocturnal severe hypoglycaemia during the last two years were included in a two-year prospective, randomised, open, multicentre, cross-over trial. A total of 149 patients were randomised 1:1 to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. Each treatment period was one year long and consisted of three months of run-in or cross-over followed by nine months of maintenance. The primary endpoint was the number of blindly adjudicated nocturnal symptomatic hypoglycaemic episodes. Secondary endpoints included the occurrence of severe hypoglycaemia. We analysed all endpoints by intention-to-treat. Results Treatment with insulin degludec resulted in a 28% (95%CI: 9-43; p=0.02) relative rate reduction (RRR) of nocturnal symptomatic hypoglycaemia at level 1 (≤3.9 mmol/L), a 37% (95%CI: 16-53; p=0.002) RRR at level 2 (≤3.0 mmol/l), and a 35% (95%CI: 1-58; p=0.04) RRR in all-day severe hypoglycaemia compared to insulin glargine U100. Conclusions/interpretation Patients with T1D prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia and all-day severe hypoglycaemia with insulin degludec as compared with insulin glargine U100. This article is protected by copyright. All rights reserved.

Background and Aims: Insulin Degludec (IDeg) , in comparison with Insulin Glargine U100 (IGla) , reduces the risk of hypoglycemic events in people with type 1 diabetes (T1D) . The impact on CGM assessed glycemic metrics: the coefficient of variation (CV) , time in range (TIR) , time below range (TBR) , and time-above range (TAR) is less known. We present CGM results from the HypoDeg trial comparing treatment with IDeg and IGla in people with T1D and recurrent nocturnal severe hypoglycemia. Materials and Methods: This is a pre-defined optional substudy of the HypoDeg trial: a 2-year investigator-initiated, randomized, cross-over trial comparing treatment with IDeg or IGla in 149 participants with T1D and at least one nocturnal severe hypoglycemic event within the last two years. Participants underwent 2 x 6 days of blinded CGM (Medtronic iPro) in each treatment arm after 6 and 12 months of treatment. Seventy-four participants completed at least one CGM period in each treatment arm. The endpoints were CV, TIR (3.9 - 10.0 mmol/L) , TBR at level 2 (< 3.0 mmol/L) and TAR (>10.0mmol/L, >13.9mmol/L) . Time spent in, below, or above range provided as percentage of readings. Results: We collected 261 CGM traces with a mean (SD) observation period of 5.9 (0.7) days. The all-day CV was lower with IDeg than IGla, with a mean (SE) CV of 40.5% (0.9) and 42.5% (0.9) , respectively (p=0.009) . A difference in CV during the night (23:00h to 07:00h) drove this, with a mean CV of 35.7% (1.1) for IDeg versus 39.6% (1.1) for IGla (p=0.001) . The all-day level 2 TBR was lower with IDeg than IGla, with a mean TBR of 1.8% (0.4) and 3.1% (0.4) , respectively (p=0.001) . The percentages of TIR and TAR were not different between treatments. Conclusion: In people with T1D prone to nocturnal severe hypoglycemia, treatment with IDeg results in a lower mean CV, reaching the definition of stable glucose levels during the night and a lower all-day TBR than IGla. Disclosure J.M.Brøsen: None. S.Lerche: None. K.Nørgaard: Advisory Panel; Medtronic, Novo Nordisk A/S, Consultant; Novo Nordisk A/S, Research Support; Dexcom, Inc., Medtronic, Novo Nordisk A/S, Zealand Pharma A/S, Speaker's Bureau; Medtronic, Stock/Shareholder; Novo Nordisk A/S. L.Tarnow: None. B.Thorsteinsson: None. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. R.Agesen: Employee; Novo Nordisk A/S. A.Alibegovic: Employee; Novo Nordisk A/S, Novo Nordisk A/S. H.U.Andersen: Advisory Panel; Abbott Diabetes, Stock/Shareholder; Novo Nordisk A/S. P.Gustenhoff: Advisory Panel; Abbott Diagnostics. T.K.Hansen: None. C.Hedetoft: None. C.R.Stolberg: None. C.B.Juhl: None. Funding Novo Nordisk

To investigate whether the long-acting insulin analogue insulin degludec compared with insulin glargine U100 reduces the risk of nocturnal symptomatic hypoglycaemia in patients with type 1 diabetes (T1D).Adults with T1D and at least one episode of nocturnal severe hypoglycaemia during the last 2 years were included in a 2-year prospective, randomized, open, multicentre, crossover trial. A total of 149 patients were randomized 1:1 to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. Each treatment period lasted 1 year and consisted of 3 months of run-in or crossover followed by 9 months of maintenance. The primary endpoint was the number of blindly adjudicated nocturnal symptomatic hypoglycaemic episodes. Secondary endpoints included the occurrence of severe hypoglycaemia. We analysed all endpoints by intention-to-treat.Treatment with insulin degludec resulted in a 28% (95% CI: 9%-43%; P = .02) relative rate reduction (RRR) of nocturnal symptomatic hypoglycaemia at level 1 (≤3.9 mmol/L), a 37% (95% CI: 16%-53%; P = .002) RRR at level 2 (≤3.0 mmol/L), and a 35% (95% CI: 1%-58%; P = .04) RRR in all-day severe hypoglycaemia compared with insulin glargine U100.Patients with T1D prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia and all-day severe hypoglycaemia with insulin degludec compared with insulin glargine U100.

Summary: Some studies indicate potential beneficial effects of metformin on body composition and bone. This trial compared metformin + insulin vs placebo + insulin. Metformin treatment had a small but positive effect on bone quality in the peripheral skeleton, reduced weight gain, and resulted in a more beneficial body composition compared with placebo in insulin-treated patients with type 2 diabetes. Introduction: Glucose-lowering medications affect body composition. We assessed the long-term effects of metformin compared with placebo on whole body bone and body composition measures in patients with type 2 diabetes mellitus. Methods: This was a sub-study of the Copenhagen Insulin and Metformin Therapy trial, which was a double-blinded randomized placebo-controlled trial assessing 18-month treatment with metformin compared with placebo, in combination with different insulin regimens in patients with type 2 diabetes mellitus (T2DM). The sub-study evaluates the effects on bone mineral content (BMC), density (BMD), and body composition from whole body dual-energy X-ray absorptiometry (DXA) scans which were assessed at baseline and after 18 months. Results: Metformin had a small, but positive, (p < 0.05) effect on subtotal, appendicular, and legs BMC and BMD compared with placebo. After adjustment for sex, age, vitamin D, smoking, BMI, T2DM duration, HbA1c, and insulin dose, the effects on appendicular BMC and BMD persisted (p < 0.05 for both). The changes in appendicular BMC and BMD corresponded approximately to a 0.7% and 0.5% increase in the metformin group and 0.4% and 0.4% decrease in the placebo group, respectively. These effects were mostly driven by an increase in BMC and BMD in the legs and a loss of BMC and BMD in the arms. During 18 months, all participants increased in weight, fat mass (FM), FM%, and lean mass (LM), but decreased in LM%. The metformin group increased less in weight (subtotal weight (weight-head) − 2.4 [− 3.5, − 1.4] kg, p value < 0.001) and FM (− 1.5 [− 2.3, − 0.8] kg, p value < 0.001) and decreased less in LM% (0.6 [0.2, 1.1] %, p value < 0.001) compared with the placebo group. Conclusion: Metformin treatment had a small positive effect on BMC and BMD in the peripheral skeleton and reduced weight gain compared with placebo in insulin-treated patients with T2DM.

Background and Aims: The risk of nocturnal hypoglycemia (NH) is a limiting factor for achieving good glycemic control in people with type 1 diabetes (T1D). Insulin degludec (IDeg) is proven to lower the risk of self-reported NH. As most episodes of NH are asymptomatic, we assessed differences in occurrence of NH by hourly plasma glucose (PG) measurements at treatments with IDeg or insulin glargine U100 (IGlar) in people with T1D suffering from recurrent nocturnal severe hypoglycemia. Materials and Methods: Pre-defined optional substudy of the HypoDeg trial, a 2-year investigator-initiated, randomized, cross-over trial where 149 participants with T1D were randomized to treatment with IDeg or IGlar. Fifty-one participants (mean (SD) age 58 (13) years, diabetes duration 28 (14) years and HbA1c 7.8 (1) %) were admitted for two nights for hourly blinded plasma glucose measurements for a minimum of one night (23:00h to 07:00h) during each 1-year treatment period. The primary endpoints were NH at level 1 (PG ≤ 3.9 mmol/L) and level 2 (PG < 3.0 mmol/L). Results: We collected data from 196 nights. A total of 57 nights (regardless of level) in 33 participants were hypoglycemic, including 20 nights with symptomatic hypoglycemia. The incidence of NH at level 1 was lower when treated with IDeg [17 events in 97 nights (18%)] as compared to IGlar [36 events in 99 nights (36%)], corresponding to a hazard ratio (HR) of 0.39 (95% CI: 0.22-0.71; p=0.002) during treatment with IDeg. At level 2, the incidence of NH was also lower during treatment with IDeg [8 events in 97 nights (8%)] as compared to IGlar [20 events in 99 nights (20%)], corresponding to an HR of 0.36 [95% CI: 0.16-0.80; p=0.013] during treatment with IDeg. Conclusion: In people with T1D and recurrent nocturnal severe hypoglycemia, treatment with IDeg as compared to IGlar results in a clinically significant lower rate of NH at both levels of hypoglycemia. Disclosure J. M. Brøsen: None. S. Lerche: None. K. Nørgaard: Advisory Panel; Self; Medtronic, Other Relationship; Self; Novo Nordisk Inc., Zealand Pharma A/S, Speaker’s Bureau; Self; Medtronic. H. D. Parving: None. L. Tarnow: None. B. Thorsteinsson: None. U. Pedersen-bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi-Aventis, Consultant; Self; Abbott, Speaker’s Bureau; Self; Novo Nordisk A/S. R. Agesen: Employee; Self; Novo Nordisk. P. L. Kristensen: Speaker’s Bureau; Self; AstraZeneca, Eli Lilly and Company. A. Alibegovic: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. H. U. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S. P. Gustenhoff: None. C. Hedetoft: None. T. Jensen: Stock/Shareholder; Self; Novo Nordisk A/S. C. B. Juhl: None. Funding Novo Nordisk

BACKGROUND Clinical characteristics such as HbA1c , systolic blood pressure (SBP), albuminuria and estimated glomerular filtration rate (eGFR) are important when treating type 1 diabetes. We investigated the variability in these measures as risk markers for micro- and macrovascular complications. METHODS This prospective study included 1062 individuals with type 1 diabetes. Visit-to-visit variability of HbA1c , SBP, albuminuria and eGFR was calculated as the SD of the residuals in individual linear regression models using all available measures in a specified period of 3 years (VV). Endpoints included were as follows: cardiovascular events (CVE) defined as myocardial infarction, non-fatal stroke, or coronary or peripheral arterial intervention; end-stage kidney disease (ESKD) defined as eGFR

OBJECTIVE Trimethylamine N-oxide (TMAO) is suggested as an independent gut microbiota–derived risk factor for cardiovascular and renal disease. We investigated associations between plasma TMAO concentrations and cardio-renal outcomes in a prospective study of individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS Plasma TMAO was measured at baseline in 1,159 individuals with type 1 diabetes (58% male, mean ± SD age 46 ± 13 years). End points were all-cause and cardiovascular mortality, cardiovascular disease (CVD), and renal events tracked from national registries. Associations between TMAO and end points were tested using Cox regression models. RESULTS After 15.0 (6.7–19.3) (median [interquartile range]) years of follow-up, we recorded all-cause and cardiovascular mortality (n = 363 and 120, respectively), combined CVD (n = 406), coronary outcome (myocardial infarction and coronary intervention) (n = 163), stroke (n = 115), hospitalization for heart failure (n = 81), and end-stage renal disease (n = 144). In univariate analyses, higher TMAO concentrations were associated with all end points (P ≤ 0.005). Except for stroke and heart failure, all end points remained significantly associated with higher TMAO concentrations after adjustment for conventional cardiovascular risk factors (P ≤ 0.003). After further adjustment for baseline estimated glomerular filtration rate (eGFR), results became insignificant for all end points. TMAO was inversely associated with baseline eGFR (R2 = 0.29; P < 0.001). CONCLUSIONS In individuals with type 1 diabetes, higher concentrations of plasma TMAO were associated with mortality, CVD events, and poor renal outcome, independent of conventional risk factors. However, the association became insignificant after further adjustment for baseline eGFR. This could reflect TMAO as a renal function marker or a risk factor for micro- and macrovascular complications mediated through impaired renal function.

BACKGROUND: The LeucoPatch device uses bedside centrifugation without additional reagents to generate a disc comprising autologous leucocytes, platelets, and fibrin, which is applied to the surface of the wound. We aimed to test the effectiveness of LeucoPatch on the healing of hard-to-heal foot ulcers in people with diabetes.METHODS: This was a multicentre, international, observer-masked, randomised controlled trial of people with diabetes and a hard-to-heal foot ulcer done in 32 specialist diabetic foot clinics in three countries (UK, Denmark, and Sweden). After a 4-week run-in period, those with a reduction in ulcer area of less than 50% were randomly allocated (1:1) by computer-generated, web-based randomisation (block sizes of two, four, and six) to either prespecified good standard care alone or care plus weekly application of LeucoPatch. The primary outcome was the proportion of ulcers that healed within 20 weeks assessed in the intention-to-treat population (all participants with post-randomisation data collected), defined as complete epithelialisation (confirmed by an observer who was masked to randomisation group), and remained healed for 4 weeks. This trial is registered with the ISRCTN registry, number 27665670, and ClinicalTrials.gov, number NCT02224742.FINDINGS: Between Aug 30, 2013, and May 3, 2017, 269 participants were randomly allocated to receive treatment (137 to receive standard care and 132 to receive LeucoPatch). The mean age was 61·9 years (SD 11·6), 217 (82%) were men, and 222 (83%) had type 2 diabetes. In the LeucoPatch group, 45 (34%) of 132 ulcers healed within 20 weeks versus 29 (22%) of 134 ulcers in the standard care group (odds ratio 1·58, 96% CI 1·04-2·40; p=0·0235) by intention-to-treat analysis. Time to healing was shorter in the LeucoPatch group (p=0·0246) than in the standard care group. No difference in adverse events was seen between the groups. The most common serious adverse event (SAE) was diabetic foot infection (24 events in the LeucoPatch group [24% of all SAEs] and 20 in the standard care group [27% of all SAEs]. There were no device-related adverse events.INTERPRETATION: The use of LeucoPatch is associated with significant enhancement of healing of hard-to-heal foot ulcers in people with diabetes.FUNDING: Reapplix ApS.

Aim Obstructive sleep apnoea (OSA) is frequent in type 2 diabetes (T2D). The aim was to investigate the effect of a 12‐week treatment with continuous positive airway pressure (CPAP) on glycaemic control assessed by continuous glucose monitoring (CGM), HbA1c and fasting blood glucose in patients with T2D and newly detected OSA. Methods In a randomized controlled multicentre study, 72 participants with T2D and moderate to severe OSA (78% male, age 62 ± 7, AHI 35 ± 15) were recruited from outpatient clinics in three Danish hospitals and were randomized to CPAP intervention or control. The main outcome was glycaemic control assessed by 6 days CGM at baseline and after 12‐week therapy, as well as by HbA1c and fasting blood glucose. Results No significant changes were found in average glucose levels, time in glucose range, time with hypoglycaemia, time with hyperglycaemia or coefficient of variability. HbA1c decreased 0.7 mmol/mol (0.07%; P = .8) in the CPAP group and increased 0.8 mmol/mol (0.08%; P = .6) in the control group (intergroup difference, P = .6). Fasting blood glucose increased by 0.2 mmol/L (P = .02) in the CPAP group and by 0.4 mmol/L (P = .01) in the control group (intergroup difference, P = .7). In a prespecified subgroup analysis comparing participants with high adherence (minimum usage of four hours/night for 70% of all nights) to CPAP to the control group, no significant changes were observed either, although these participants had a tendency towards better glycaemic indices. Conclusions CPAP treatment for 12 weeks does not significantly change glycaemic control in patients with type 2 diabetes and OSA., Former studies show a high prevalence of obstructive sleep apnoea (OSA) in people with type 2 diabetes (T2D). Previous data are divergent on whether continuous positive airway pressure (CPAP) therapy improves glycaemic control in people with T2D and OSA. In this randomized controlled study, no effect was found of 12‐week CPAP treatment on glycaemic control measured by continuous glucose monitoring, HbA1c and fasting blood glucose. This study does not support implementation of routine CPAP to people with T2D and OSA with the purpose of improving glycaemic control.

IntroductionA physically active lifestyle during pregnancy improves maternal and offspring health but can be difficult to follow. In Denmark, less than 40% of pregnant women meet physical activity (PA) recommendations. The FitMum study aims to explore strategies to increase PA during pregnancy among women with low PA and assess the health effects of PA. This paper presents the FitMum protocol, which evaluates the effects of structured supervised exercise training or motivational counselling supported by health technology during pregnancy on PA level and health of mother and offspring.Methods and analysisA single-site three-arm randomised controlled trial that aims to recruit 220 healthy, pregnant women with gestational age (GA) no later than week 15 and whose PA level does not exceed one hour/week. Participants are randomised to one of three groups: structured supervised exercise training consisting of three weekly exercise sessions, motivational counselling supported by health technology or a control group receiving standard care. The interventions take place from randomisation until delivery. The primary outcome is min/week of moderate-to-vigorous intensity PA (MVPA) as determined by a commercial activity tracker, collected from randomisation until GA of 28 weeks and 0-6 days, and the secondary outcome is gestational weight gain (GWG). Additional outcomes are complementary measures of PA; clinical and psychological health parameters in participant, partner and offspring; analyses of blood, placenta and breastmilk samples; process evaluation of interventions; and personal understandings of PA.Ethics and disseminationThe study is approved by the Danish National Committee on Health Research Ethics (# H-18011067) and the Danish Data Protection Agency (# P-2019-512). Findings will be disseminated via peer-reviewed publications, at conferences, and to health professionals via science theatre performances.Trial registration numberNCT03679130.Protocol versionThis paper was written per the study protocol version 8 dated 28 August 2019.

BACKGROUND There is a high prevalence of unexplained and unexplored obstructive sleep apnea (OSA) among patients with type 2 diabetes. The daytime symptoms of OSA include severe fatigue, cognitive problems, a decreased quality of life, and the reduced motivation to perform self-care. These symptoms impair the management of both diabetes and daily life. OSA may therefore have negative implications for diabetes self-management. Continuous positive airway pressure (CPAP) therapy is used to treat OSA. This treatment improves sleep quality, insulin resistance, and glycemic control. Although the benefits of using CPAP as a treatment for OSA are clear, the noncompliance rate is high, and the evidence for the perceived effect that CPAP treatment has on patients with type 2 diabetes and OSA is poor. OBJECTIVE The purpose of this study was to analyze the impacts that comorbid diabetes and OSA have on the daily lives of older adults and to investigate the perceived effect that CPAP treatment for OSA has on patients’ diabetes self-management. METHODS A qualitative follow-up study that involved in-depth, semistructured dyad interviews with couples before and after CPAP treatment (N=22) was conducted. Patients were recruited from the Hilleroed Hospital in Denmark and were all diagnosed with type 2 diabetes, aged >18 years, and had an apnea-hypopnea index of ≥15. All interviews were coded and analyzed via thematic analysis. RESULTS The results showed that patients and their partners did not consider OSA to be a serious disorder, as they believed that OSA symptoms were similar to those of the process of aging. Patients experienced poor nocturnal sleep, took frequent daytime naps, exhibited reduced cognitive function, and had low levels of physical activity and a high-calorie diet. These factors negatively influenced their diabetes self-management. Despite the immediate benefit of CPAP treatment, most patients (11/12, 92%) faced technical challenges when using the CPAP device. Only the patients with severe OSA symptoms that affected their daily lives overcame the challenges of using the CPAP device and thereby improved their diabetes self-management. Patients with less severe symptoms rated CPAP-related challenges as more burdensome than their symptoms. CONCLUSIONS If used correctly, CPAP has the potential to significantly improve OSA, resulting in better sleep quality; improved physical activity; improved diet; and, in the end, better diabetes self-management. However, there are many barriers to undergoing CPAP treatment, and only few patients manage to overcome these barriers and comply with correct treatment.

Background There is a high prevalence of unexplained and unexplored obstructive sleep apnea (OSA) among patients with type 2 diabetes. The daytime symptoms of OSA include severe fatigue, cognitive problems, a decreased quality of life, and the reduced motivation to perform self-care. These symptoms impair the management of both diabetes and daily life. OSA may therefore have negative implications for diabetes self-management. Continuous positive airway pressure (CPAP) therapy is used to treat OSA. This treatment improves sleep quality, insulin resistance, and glycemic control. Although the benefits of using CPAP as a treatment for OSA are clear, the noncompliance rate is high, and the evidence for the perceived effect that CPAP treatment has on patients with type 2 diabetes and OSA is poor. Objective The purpose of this study was to analyze the impacts that comorbid diabetes and OSA have on the daily lives of older adults and to investigate the perceived effect that CPAP treatment for OSA has on patients’ diabetes self-management. Methods A qualitative follow-up study that involved in-depth, semistructured dyad interviews with couples before and after CPAP treatment (N=22) was conducted. Patients were recruited from the Hilleroed Hospital in Denmark and were all diagnosed with type 2 diabetes, aged >18 years, and had an apnea-hypopnea index of ≥15. All interviews were coded and analyzed via thematic analysis. Results The results showed that patients and their partners did not consider OSA to be a serious disorder, as they believed that OSA symptoms were similar to those of the process of aging. Patients experienced poor nocturnal sleep, took frequent daytime naps, exhibited reduced cognitive function, and had low levels of physical activity and a high-calorie diet. These factors negatively influenced their diabetes self-management. Despite the immediate benefit of CPAP treatment, most patients (11/12, 92%) faced technical challenges when using the CPAP device. Only the patients with severe OSA symptoms that affected their daily lives overcame the challenges of using the CPAP device and thereby improved their diabetes self-management. Patients with less severe symptoms rated CPAP-related challenges as more burdensome than their symptoms. Conclusions If used correctly, CPAP has the potential to significantly improve OSA, resulting in better sleep quality; improved physical activity; improved diet; and, in the end, better diabetes self-management. However, there are many barriers to undergoing CPAP treatment, and only few patients manage to overcome these barriers and comply with correct treatment.

We studied the implementation of recommended yearly control visits, quality of care and characteristics and co-morbidities of patients with chronic obstructive lung disease (COPD), Type 2 diabetes mellitus (T2DM) and those with both conditions in a sample of Danish general practices.This was a retrospective audit of patient records from 2017 in 164 general practices in Denmark. Up to 15 patients were randomly selected in each practice for assessment of relevant parameters and quality of care, producing a total of 820 patients with COPD, 823 patients with T2DM and 709 patients with both COPD and T2DM.Formalised annual control visits were completed in 72% of the patients with T2DM and 48% of the patients with COPD. Approximately 13% of the patients were followed by a specialist. Patients with both diseases had the highest number of healthcare contacts but the lowest fulfilment of annual control visits. The standard of care was fair, although assessment of the disease characteristics of COPD was less complete in patients with both conditions. Cardiovascular diseases including heart failure were significantly more common in patients with both conditions (42%) than in those with COPD only (29%) or T2DM only (27%).In 2017, the implementation of annual control visits for COPD was less complete than for T2DM. Patients with both diseases had the highest prevalence of cardiovascular disease and use of health resources, suggesting that this group needs additional attention.The present study was sponsored by Boehringer Ingelheim Denmark.not relevant.

Introduction: Adults with diabetes have a two to four folds increased risk of dying with heart disease compared to those without diabetes. Higher cardiac troponins, especially Troponin T (TnT) is a specific biomarker for cardiac injury also guiding management of chest pain and associated with increased risk of heart failure. Hypothesis: There is limited knowledge on genes regulating cardiac TnT levels. We conducted a genome wide association study (GWAS) for circulating cardiac TnT levels among individuals with type 1 diabetes (T1D). Methods: The study included 849 T1D individuals recruited from the outpatient clinic at Steno Diabetes Center Copenhagen, Denmark. Serum high sensitive TnT (hsTnT) levels were measured and log transformed for normalization after check for outliers (mean ± 4 SD). Genotyping on 538,448 single nucleotide variants (SNVs) was done using Illumina Human Core Exome Chip. After quality control filters: hardy weinberg equilibrium (p >10 -6 ), European ancestry, genotype call rates >95%, common variants were examined in 740 individuals with hs TnT data. We ran linear regression based additive genetic models adjusting for age, sex, diabetes duration and population sub structure using Plink and R statistical programs. P -8 was genome wide significant (GWS) while 5 x 10 -8 < p < 1 x 10 -6 was considered suggestive. Results: Participants had a mean (SD) age of 43.7 (11.1) years, 57.4% were men, with diabetes duration of 28.0 (9.5) years, HbA1c 8.9 (1.3) % and 50.5% with diabetic nephropathy. Median (IQR) hsTnT levels were 64.7 (29.2-175.6) pg/ml. We identified a GWS missense common variant in the CISD3 gene locus on chromosome 17 (p=1.7 x 10 -8 ) for cardiac hsTnT levels. This gene codes CDGSH Iron Sulfur Domain 3 protein also called Mitochondrial Inner NEET Protein. Two suggestive loci were PTPRD (Protein Tyrosine Phosphatase Receptor Type D; p=4.9 x 10 -7 ) and DCC (DCC Netrin 1 Receptor; 6.6 x 10 -7 ) on chromosomes 9 and 18. PTPRD is a known GWS locus for hsTnT that we reconfirm among T1D individuals. Conclusions: We identify a novel gene locus for circulating cardiac hsTnT levels among T1D individuals of European ancestry. CISD3 is expressed in heart tissue regulating mitochondrial functions. Further validation is suggested.

Introduction: Lipohypertrophy (LH) is caused by repetitively injecting insulin into the same location. This can lead to unpredictable insulin absorption and increased glucose variability (GV). A new medical device, ROTO Track, automatically guides the user to rotate abdominal insulin injections to avoid LH lesions. This study aimed to test whether the medical device could reduce the number of insulin injections in the same subcutaneous area as compared with non-aided standard insulin injection techniques. Methods: In this proof-of-concept cross-over study, baseline data about injection site in the abdominal region were collected blinded for 1 week with a nonguiding version of the device and compared to 1 and 12 weeks of device guidance in 35 people with type 1 diabetes. The device registered time and location of abdominal injections. The primary endpoint was a “rotation score.” Secondary endpoints included number and size of LH, GV, and hemoglobin A1c. Results: The rotation score improved significantly from a baseline mean of 40.2% to 49.9% after 1 week (confidence interval: 2.2-17.2%, P = .012) and improved further after 12 weeks to 52.2% ( P < .001). After 12 weeks, LH was reduced both in median size from 9.2 (range: [0.9-29.4]) cm2 to 5.4 (range: [0.0- 26.8]) cm2 ( P = .041) and mean count from 1.4 (range: [1-2]) to 1.1 (range: [0-2], P = .039) and the coefficient of variation of interstitial glucose was reduced from 38.6 to 35.1 ( P = .009). Conclusion: This proof-of-concept study indicates that the device improves rotation of insulin injections, and reduces LH and GV.

Obstructive sleep apnoea (OSA) is associated with excessive daytime sleepiness and therefore affects traffic safety. The risk factors for OSA are age and BMI, and therefore sedentary occupational groups are likely to have a high prevalence of OSA. Our aim was to investigate the prevalence and identify the risk factors for OSA and Type 2 diabetes (T2D) among occupational truck drivers in Denmark.Occupational truck drivers were recruited and their pulse oximetry and nasal respiratory flow were measured with the ApneaLink device. The Apnea-Hypopnea Index (AHI), defined as the average number of apnoeas and hypopnoeas per hour of sleep, was used to classify 1) non OSA (AHI less-than 5/h), 2) mild OSA (5/h ≤ AHI less-than 15/h), 3) moderate OSA (15/h ≤ AHI ≤ 30/h) and 4) severe OSA (AHI30/h). Risk factors for OSA and T2D were investigated by linear and logistic regressions.A total of 57 of 97 drivers were included in the analysis, all of whom were men, and 56% had OSA. The linear regressions showed all of the evaluated risk factors to be positively associated (less-than 0.01) with the AHI score, supported by the estimated odds ratios of having above-recommended levels of the evaluated risk factors when classified as having OSA.All the evaluated risk factors were significantly associated with AHI, and the prevalence of OSA was above mean levels in the population. Confirmation of these results is warranted in future studies.This study was supported by unrestricted grants from The FDE foundation, The Danish Council for Safe Traffic and Nordsjaellands Hospital.none.

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.

Carotid intima-media thickness (IMT) can assess the cumulative effect of atherosclerotic risk factors and provides an independent predictor of future cardiovascular (CV) risk. The aim of this study was to investigate the progression of conventional risk factors in 933 long-term survivors from a Danish cohort with and without diabetes mellitus (DM) as predictors for attained carotid IMT during 35.6 (0.7) years of follow-up. Persons who participated in the first, the last and one of the intermediate rounds of the Copenhagen City Heart Study, and who had had an ultrasound-derived measure of the carotid IMT performed at the last examination were included in the analyses. The risk factors varied between persons with and without DM during the 36 years, but the difference in blood pressure disappeared in the fifth examination, where, in addition, total cholesterol was found to be lower in persons with DM. In this cohort there were no difference in attained carotid IMT between persons with and without DM at the last examination. The following risk factors were found to best predict carotid IMT: age, maximum systolic BP, average systolic BP, average BMI, minimum BMI, sex and years of smoking. The prediction of carotid IMT was clinically poor with a root mean-squared error of prediction (RMSEP) of 0.134 mm and a 95% prediction error probability interval of (-0.22; 0.30). Furthermore, the distribution of prediction errors was skewed to the right indicating that the prediction errors were larger among persons with high carotid IMT.

Lipohypertrophy (LH), a common side effect of insulin therapy, is caused by repetitively injecting insulin into the same location. When insulin is injected into LH lesions, the absorption of insulin may be erratic and unpredictable, which can lead to unexpected hyperglycemia and hypoglycemia and increased blood glucose variability. To improve injection techniques and avoid LH, a new medical device, ROTO Track® which automatically guides the person with diabetes to rotate the abdominal insulin injections was tested. The hypothesis is that the device can reduce the number of insulin injections in the same subcutaneous area as compared with non-aided standard insulin injection techniques in people with T1DM. Methods: In this proof-of-concept cross-over study, baseline data about injection site in the abdominal region was collected blinded for one week with a non-guiding version of the device and compared to 12 weeks of device guidance in 35 people with T1DM. The device registered injection time and location on the abdomen. Based on this a "rotation score", the primary endpoint, was calculated. Secondary end points included number and size of LH, glycemic variability and HbA1c. LH sizes were documented by drawing on a wound care grid after palpation of the skin. Interstitial glucose was measured with a continuous glucose monitor and the coefficient of variation, CV was calculated. Results: The rotation score improved significantly from a baseline mean of 40.2% to 49.9% after one week (CI: 2.2% - 17.2%, p=0.012) and improved further after 12 weeks to 52.2% (p After 12 weeks, LH was reduced both in mean size from 11.9 (+/- 9.5) cm2 to 8.2 (+/- 9.7) cm2 (p=0.041) and numbers (p=0.039) and the CV of interstitial glucose was reduced from 38.6 to 35.1 (p=0.009). There were no changes in mean interstitial glucose, HbA1c or hypoglycemic events after 12 weeks. Conclusion: This proof-of-concept study indicates that the device is safe, improves rotation, reduces LH and reduces glycemic variability. Disclosure C.K. Klarskov: None. Y.H. Hamid: None. R.T. Tjalk-Bøggild: Board Member; Self; ROTO Health ApS. Employee; Self; ROTO Health ApS. L. Tarnow: None. P.L. Kristensen: None. Funding Innovation Fund Denmark (8063-00049B); Nordic Healthcare Technology

Background and Aims: The long-acting insulin analog degludec reduces the risk of nocturnal hypoglycemia in patients with type 1 diabetes (T1D). The HypoDeg trial compared the effect of insulin degludec to insulin glargine U100 on frequency of nocturnal hypoglycemia in T1D patients with recurrent nocturnal severe hypoglycemia and reported a significant 37% relative risk reduction (RRR) of symptomatic nocturnal hypoglycemia ≤ 3.0 mmol/L with insulin degludec. Here we report the data on severe hypoglycemia (SH). Materials and Methods: In this investigator-initiated, prospective, randomized, open-label, blinded-endpoint crossover trial conducted at 10 centers in Denmark, we recruited 149 T1D patients (>18 years) with ≥2 episodes of nocturnal SH in the preceding two year. Patients were randomly assigned (1:1) to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. A 1-year plus 1-year treatment period was specified, consisting of two 3-month run-in periods, each followed by a 9-month maintenance period. Episodes of SH were reported by telephone and adjudicated blinded to treatment. Results: A total of 136 SH episodes were reported during the maintenance periods: 56 (41%) episodes during treatment with insulin degludec and 80 (59%) episodes during treatment with insulin glargine U100, resulting in a RRR of 35% (95% confidence interval [CI]: 0-60%; p=0.04). This corresponds to an absolute rate reduction of 0.3 episodes (95% CI: 0.0-0.5) per patient-year with insulin degludec. The difference was primarily due to a lower risk of nocturnal episodes (RRR 52%, 95% CI: -10-80%; p=0.08), whereas there was no difference during daytime (RRR 10%, 95% CI: -80-50%; p=0.75). Conclusion: Treatment with insulin degludec in T1D patients with recurrent nocturnal SH resulted in a clinically significant reduced rate of SH compared with insulin glargine U100. Disclosure R.M. Agesen: Employee; Self; Novo Nordisk A/S. A. Alibegovic: Employee; Self; Novo Nordisk A/S. H.U. Andersen: Advisory Panel; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. P. Gustenhoff: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi-Aventis. T.K. Hansen: None. T. Jensen: Stock/Shareholder; Self; Novo Nordisk A/S. C.B. Juhl: None. A.K. Jensen: None. S. Lerche: None. K. Nørgaard: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Medtronic, Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk Inc. H.D. Parving: None. A.L. Sørensen: None. L. Tarnow: None. B. Thorsteinsson: None. U. Pedersen-Bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Novo Nordisk A/S. Funding Novo Nordisk A/S