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Background: Complications can be present at type 2 diabetes (T2D) diagnosis or develop later. We describe trends in burden of ischaemic heart disease (IHD) in T2D. Methods: T2D cases in Denmark 1996-2020 in a national diabetes register were used. Events of IHD 1994-2020 were from the National Patient Register. Prevalence of IHD at time of T2D was described by a binomial model. New IHD and death during follow-up were analysed by rate models and used to estimate the time in the states (no IHD / IHD at T2D / IHD after T2D) . Results: 410,4 persons with T2D 1996-2020 were included; 61,378 with pre-existing IHD. Prevalence of IHD at T2D diagnosis was increasing 1.7%/year. Incidence rates of IHD after diagnosis was decreasing 5.7%/year. Mortality among T2D persons without IHD decreased 5.7%/year; for those with IHD it decreased 3.5%/year. During the first years, expected lifetime was 8.1 and 8.8 years for men diagnosed at age 65 in 1998 and 2018, respectively. Time without IHD was 6.2 and 6.9 years, with new IHD 0.9 and 0.5 years and with preexisting IHD 1.0 and 1.5 years in 1998 and 2018. We saw an increase in expected lifetime, partly as increase in lifetime with preexisting IHD. Similar patterns were seen for women and for persons diagnosed in other ages. Conclusions: We saw an increase in expected lifetime, as well as decreasing mortality rates regardless of IHD status. Prevalence of IHD at the time of diagnosis was increasing, possibly due to more detailed diagnoses of IHD; in our data only IHD complications after 1994 are included which may be a partial explanation of the increase in prevalent IHD at the date of T2D diagnosis. In general the IHD burden in T2D in Denmark is decreasing. Disclosure B.Carstensen: Stock/Shareholder; Novo Nordisk A/S. K.K.Clemmensen: Employee; Novo Nordisk A/S, Research Support; AstraZeneca, Novo Nordisk Foundation, Stock/Shareholder; Lundbeck, Novo Nordisk A/S. H.Amadid: Stock/Shareholder; Novo Nordisk.

Aims/hypothesis: We aimed to investigate the short-term efficacy and safety of three glucose-lowering interventions in overweight or obese individuals with prediabetes defined by HbA1c. Methods: The PRE-D Trial was a randomised, controlled, parallel, multi-arm, open-label, non-blinded trial performed at Steno Diabetes Center Copenhagen, Gentofte, Denmark. One hundred and twenty participants with BMI ≥25 kg/m2, 30–70 years of age, and prediabetes (HbA1c 39–47 mmol/mol [5.7–6.4%]) were randomised 1:1:1:1 to dapagliflozin (10 mg once daily), metformin (1700 mg daily), interval-based exercise (5 days/week, 30 min/session) or control (habitual lifestyle). Participants were examined at baseline and at 6, 13 and 26 weeks after randomisation. The primary outcome was the 13 week change in glycaemic variability (calculated as mean amplitude of glycaemic excursions [MAGE]) determined using a continuous glucose monitoring system (pre-specified minimal clinically important difference in MAGE ∼30%). Results: One hundred and twelve participants attended the examination at 13 weeks and 111 attended the follow-up visit at 26 weeks. Compared with the control group, there was a small decrease in MAGE in the dapagliflozin group (17.1% [95% CI 0.7, 30.8], p = 0.042) and a small, non-significant, reduction in the exercise group (15.3% [95% CI −1.2, 29.1], p = 0.067), whereas MAGE was unchanged in the metformin group (0.1% [95% CI −16.1, 19.4], p = 0.991)). Compared with the metformin group, MAGE was 17.2% (95% CI 0.8, 30.9; p = 0.041) lower in the dapagliflozin group and 15.4% (95% CI −1.1, 29.1; p = 0.065) lower in the exercise group after 13 weeks, with no difference between exercise and dapagliflozin (2.2% [95% CI −14.8, 22.5], p = 0.815). One serious adverse event occurred in the control group (lung cancer). Conclusions/interpretation: Treatment with dapagliflozin and interval-based exercise lead to similar but small improvements in glycaemic variability compared with control and metformin therapy. The clinical importance of these findings in prediabetes is uncertain. Trial registration: ClinicalTrials.gov NCT02695810 Funding: The study was funded by the Novo Nordisk Foundation, AstraZeneca AB, the Danish Innovation Foundation, the University of Copenhagen and Ascensia Diabetes Care Denmark ApS [Figure not available: see fulltext.]

Aim: To explore how participating in a randomised controlled trial affected motivation, barriers and strategies in the process of health behaviour change among individuals with prediabetes. Methods: An extension to the PRE-D trial, a qualitative study investigated the efficacy of glucose-lowering interventions (metformin, dapagliflozin or exercise) compared with a control group among individuals with prediabetes and overweight/obesity. Data were collected through separate focus group interviews with participants using semi-structured interview guides inspired by health behaviour change theories. Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis with an inductive-deductive approach. Results: Four interrelated themes emerged from interviews: (1) 'self-construction of prediabetes', on how participants understood the term 'prediabetes', (2) 'altered health image', on how participants' health perceptions were affected, (3) 'personal strategies for health behaviour change', on different ways to attempt to implement behaviour changes and (4) 'the process of health behaviour change', on how participants progressed and relapsed while trying to change behaviour. Themes relate to the health belief model, self-determination theory, self-efficacy and the trans-theoretical model of change. Participants shared their experiences and thoughts during interviews and inspired each other, which led some participants to develop a new perspective on prediabetes severity and increased their motivation for behaviour change. Conclusions: How participants perceived and accepted, rejected or neglected prediabetes appeared to affect their health images and whether they realised a need for behaviour change. Their achievements during interventions, health literacy, self-efficacy and perceived support from their social networks, professionals and technological aids influenced the maintenance of health behaviour changes.

Aim: To assess lipid-lowering drug (LLD) use patterns during 1996-2017 and examine lipid levels in relation to the use of LLDs and prevalent atherosclerotic cardiovascular disease (ASCVD). Methods: Using a nationwide diabetes register, 404 389 individuals with type 2 diabetes living in Denmark during 1996-2017 were identified. Individuals were followed from 1 January 1996 or date of type 2 diabetes diagnosis until date of emigration, death or 1 January 2017. Redemptions of prescribed LLDs were ascertained from the nationwide Register of Medicinal Products Statistics. Data on lipid levels were sourced from the National Laboratory Database since 2010. LLD coverage was calculated at any given time based on the redeemed amount and dose. Trends in lipid levels were estimated using an additive mixed-effect model. Low-density lipoprotein cholesterol (LDL-C) goal attainment was assessed based on recommended targets by the 2011, 2016 and 2019 guidelines for management of dyslipidaemias. Results: LLD use has decreased since 2012 and only 55% of those with type 2 diabetes were LLD users in 2017. A decline in levels of total cholesterol and LDL-C, and an increase in triglycerides, was observed during 2010-2017. Annual mean levels of LDL-C were lower among LLD users compared with non-users (in 2017: 1.84 vs. 2.57 mmol/L). A greater fraction of LLD users achieved the LDL-C goal of less than 1.8 mmol/L compared with non-users (in 2017: 51.7% and 19%, respectively). Among LLD users with prevalent ASCVD, 26.9% and 55% had, as recommended by current 2019 European guidelines, an LDL-C level of less than 1.4 mmol/L and less than 1.8 mmol/L, respectively, in 2017. Conclusions: LLD use and LDL-C levels are far from optimal in the Danish type 2 diabetes population and improvement in LLD use could reduce ASCVD events.

Background: The glycocalyx lines the inner surface of the capillary endothelium. Capillaroscopy enables visualization of the sublingual capillaries and measurement of the perfused boundary region (PBR) as an estimate of the glycocalyx. Novel software enables assessment of the PBR estimated at a fixed high flow level (PBR-hf) and the microvascularity by the MicroVascular Health Score (MVHS). Damaged glycocalyx may represent microvascular damage in diabetes and assessment of its dimension might improve early cardiovascular (CV) risk stratification. Aim: To assess the associations between PBR, PBR-hf and MVHS and CV risk factors in persons with type 1 diabetes (T1D); and to compare PBR, PBR-hf and MVHS in persons with T1D and healthy controls. Methods: Cross-sectional study including 161 persons with T1D stratified by stage of diabetic kidney disease according to level of albuminuria and 50 healthy controls without diabetes. The PBR, PBR-hf and MVHS were assessed by the GlucoCheck device (valid measurements were available in 136 (84.5%) with T1D and in all the controls). Higher PBR and PBR-hf indicate smaller glycocalyx width and lower MVHS represents a worse microvascular health. Results: There were no associations between PBR, PBR-hf or MVHS and the CV risk factors in persons with T1D, except for a higher PBR-hf and a lower MVHS in females (p = 0.01 for both). There was no difference in PBR, PBR-hf or MVHS in persons with normo-, micro- or macroalbuminuria (p ≥ 0.34). PBR was higher and MVHS was lower in persons with T1D as compared to the healthy controls (p ≤ 0.02). After adjustment for CV risk factors the difference in PBR remained significant (p = 0.001). Conclusions: The endothelial glycocalyx dimension was impaired in persons with T1D compared to healthy controls. We found no association between the endothelial glycocalyx dimension and the level of albuminuria or CV risk factors among persons with T1D. The use of the GlucoCheck device in T1D may not contribute to CV risk stratification. Disclosure E. Buur stougaard: Employee; Spouse/Partner; Novo Nordisk, Stock/Shareholder; Spouse/Partner; Novo Nordisk. S. Winther: None. H. Amadid: Stock/Shareholder; Self; Novo Nordisk A/S. M. Frimodt-moeller: None. F. Persson: Advisory Panel; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Mundipharma International, Novo Nordisk, Advisory Panel; Spouse/Partner; AstraZeneca, Bristol-Myers Squibb Company, Research Support; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mundipharma International, Novo Nordisk. T. W. Hansen: Stock/Shareholder; Self; Novo Nordisk A/S. P. Rossing: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Merck KGaA, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Vifor Pharma Management Ltd. Funding Novo Nordisk Foundation (NNF14SA0003)

Knowledge on how energy intake and macronutrients are distributed during the day and the role of daily eating patterns in body composition among adults with overweight/obesity and prediabetes is lacking. Therefore, we evaluated the diurnal dietary intake and studied the associations of daily eating patterns with body fat percentage. A total of 119 adults with prediabetes were included (mean (SD) HbA1c 41 (2.3) mmol/mol, BMI 31.5 (5.0) kg/m2, age 57.8 (9.3) years, 44% men). Information on dietary intake was obtained from self-reported food records for three consecutive days. All foods and beverages (except water) were registered with information on time of ingestion. Body fat was measured by dual-energy X-ray absorptiometry. A total of 60.5% of the participants reported a daily eating window of 12 or more hours/day, and almost half of the daily total energy intake was reported in the evening. In analyses adjusted for age, gender, and total daily energy intake, having the first daily energy intake one hour later was associated with slightly higher body fat percentage (0.64% per hour, 95% CI: 0.28, 1.01, p &lt, 0.001), whereas higher meal frequency was associated with slightly lower body fat percentage (0.49% per extra daily meal, 95% CI: &minus, 0.81, &minus, 0.18, p = 0.002). Prospective studies are warranted to address the clinical implications of daily eating patterns on body fat and cardiometabolic health.

Aim: To assess the effects of dapagliflozin, metformin and exercise treatment on changes in plasma glucagon concentrations in individuals with overweight and HbA1c-defined prediabetes.Materials and Methods: One-hundred and twenty individuals with overweight (body mass index >= 25 kg/m(2)) and prediabetes (HbA1c of 39-47 mmol/mol) were randomized to a 13-week intervention with dapagliflozin (10 mg once daily), metformin (850 mg twice daily), exercise (30 minutes of interval training 5 days per week) or control (habitual living). A 75-g oral glucose tolerance test (OGTT) (0, 30, 60 and 120 minutes) was administered at baseline, at 13 weeks (end of intervention) and at 26 weeks (end of follow-up). Linear mixed effects models with participant-specific random intercepts were used to investigate associations of the interventions with fasting plasma glucagon concentration, insulin/glucagon ratio and glucagon suppression during the OGTT.Results: At baseline, the median (Q1; Q3) age was 62 (54; 68) years, median fasting plasma glucagon concentration was 11 (7; 15) pmol/L, mean (SD) HbA1c was 40.9 (2.3) mmol/mol and 56% were women. Compared with the control group, fasting glucagon did not change in any of the groups from baseline to the end of the intervention (dapagliflozin group: -5% [95% CI: -29; 26]; exercise group: -8% [95% CI: -31; 24]; metformin group: -2% [95% CI: -27; 30]). Likewise, there were no differences in insulin/glucagon ratio and glucagon suppression during the OGTT between the groups.Conclusions: In individuals with prediabetes, 13 weeks of treatment with dapagliflozin, metformin or exercise was not associated with changes in fasting or post-OGTT glucagon concentrations.

The sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin has been approved for the treatment of Type 1 diabetes (T1D) with significant reductions in HbA1c, weight, total daily insulin dose and significant increase in time in range without an increased risk of hypoglycaemia. The use of SGLT2i in T1D has, however, shown a significant increase from 1,9% to 4,0% in the risk of diabetic ketoacidosis (DKA), which may present as euglycaemic DKA. In this review we therefore find it important to know, that DKA may present with normal/near-normal blood glucose levels, if the patient is treated with an SGLT2i.

Introduction: Glucagon plays a role in the pathogenesis of type 2 diabetes. Yet, little is known about the effect of interventions aimed at preventing progression from prediabetes to diabetes on glucagon concentrations. We examined the effects of dapagliflozin, metformin or exercise on plasma glucagon concentration in individuals with HbA1c-defined prediabetes. Methods: 120 individuals were randomized to a 13-week intervention with dapagliflozin (10 mg once daily), metformin (850 mg twice daily), exercise (interval training 30 min 5 days/week) or control (habitual living). A 75 g oral glucose tolerance test (OGTT; 0, 30, 60 and 120 min) was administered at baseline, at 13 weeks (end of intervention) and at 26 weeks (end of follow-up). Linear mixed-effects models were used to assess effects on fasting concentration, early (0-30 min) area under the curve relative to the fasting level (rAUC0-30 min) and full rAUC0-120 min for glucagon. Results: At baseline, the median (Q1;Q3) age was 62 (54;68) years, HbA1c 5.9% (5.7;6.1%), fasting glucagon 11 (7;15) pmol/L, and 56% were men. No differences in the glucagon measures between groups from baseline to 13 or 26 weeks were observed (Table 1). Conclusions: 13 weeks of treatment with dapagliflozin, metformin or exercise was not associated with changes in fasting or post-OGTT glucagon concentrations in individuals with prediabetes. Disclosure K.K.B. Clemmensen: Research Support; Self; AstraZeneca, Novo Nordisk Foundation. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. M.B. Blond: None. H. Amadid: None. L.B. Nielsen: None. D. Vistisen: Stock/Shareholder; Self; Novo Nordisk A/S. K. Karstoft: Employee; Spouse/Partner; Novo Nordisk A/S. F. Persson: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Research Support; Self; Amgen, AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S. M. Ried-Larsen: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Novo Nordisk Foundation. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp. S.S. Torekov: Research Support; Self; Novo Nordisk Inc. J.S. Quist: None. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. K. Færch: None. Funding Novo Nordisk Foundation; AstraZeneca; University of Copenhagen; Innovation Foundation

Background and aim: Both micro- and macro vascular complications represent major problems for diabetes patients and monitoring of the extent of these among diabetes patients is essential. Several studies have reported decreasing complications rates. We describe the burden and trend in 18 groups of complications in persons with diabetes in Denmark 1996-2016. Methods: We compiled a diabetes register for the entire Danish population, including reliable classification of type of diabetes. From the National Patient Register we extracted dates of recorded complications in 18 classes. Binomial regression was used to describe the prevalence of complications at diagnosis and change in these over time. Rate models based on Poisson likelihood were used to describe the incidence rates and changes in these. Analyses were conducted separately for T1D and T2D, and controlled for sex, age, duration of diabetes and including a linear term to describe the calendar time effect (date of diagnosis). Results: The prevalence at diagnosis of previous CVD was 10% in T1D and 37% in T2D, with annual relative changes of 3% in T1D and 5% in T2D. Retinopathy prevalence at diagnosis was 4.3% in T1D and 1.7% in T2D with no change in T1D, but a relative decrease of 6% in T2D. We found similar decreases in rates of complications in T1D and T2D; decrease of 2%/year in rates of CVD, 5%/year in amputations, while there were no changes in the incidence rates of retinopathy and renal disease over the period 1996-2016. For most complications we found a very high incidence during the first year after diagnosis, most likely reflecting a diagnostic catch-up and not any biological phenomenon. Conclusions: A steady decrease in incidence rates of most complications was seen, but not for microvascular complications. The pattern of complications at diagnosis was more mixed, influenced by fluctuations in diagnostic activity over the period. In general an encouraging trend in complication occurrence was seen in Denmark in the period 1996-2016. Disclosure B. Carstensen: Stock/Shareholder; Self; Novo Nordisk A/S. H. Amadid: None. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S.

Background: Lipid-lowering treatment is crucial in preventing cardiovascular disease in type 2 diabetes subjects. It is unknown how well treatment guidelines translate into clinical practice. We examined measured lipid levels in relation to use of lipid-lowering drugs among type 2 diabetes subjects in Denmark from 2010 to 2017. Methods: The study population consisted of 404,389 subjects with type 2 diabetes living in Denmark between 1996 and 2017 identified using the Danish Diabetes Register. Redemptions of prescribed lipid-lowering drugs were ascertained from the nationwide Register of Medicinal Products Statistics. Data on lipid levels was sourced from the National Laboratory Database containing detailed information on laboratory measurements at major clinical laboratories since 2010. A drug-exposure function was developed and applied to examine follow-up of lipid-lowering drug coverage at any given time based on the redeemed amount and dose of lipid-lowering drugs. Annual mean lipid levels were obtained by calculating the mean lipid measurement value per subject, per calendar year, and per lipid type. Proportions of subjects within LDL thresholds were calculated according to thresholds defined by 2019 European Society of Cardiology dyslipidemia guidelines. Results: In total, 64% of subjects redeemed at least two prescriptions of lipid-lowering drugs during the study period. A decline in levels of total-cholesterol and LDL was observed in the years from 2010 to 2017 in users and non-users of lipid-lowering drugs. Annual mean LDL levels were lower among lipid-lowering drug users compared with non-users (in 2017: 1.84 and 2.57 mmol/L, respectively). A greater fraction of lipid-lowering drug users achieved the LDL goal of Conclusions: Lipid-lowering drug use and LDL levels are far from optimal in the Danish type 2 diabetes population and constitute a large potential for improvement. Disclosure H. Amadid: None. M. Bekker-Nielsen Dunbar: None. P.F. Rønn: Research Support; Self; Amgen, Danish Diabetes Academy. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. J.S. Knudsen: None. B. Carstensen: Stock/Shareholder; Self; Novo Nordisk A/S. F. Persson: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Research Support; Self; Amgen, AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. Funding Amgen Inc.

Background: Plasma levels of liver enzymes are elevated in prediabetes but may improve in response to weight loss and glucose-lowering interventions. We examined the effects of dapagliflozin, metformin, or exercise on plasma levels of alanine transferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) in people with prediabetes. Methods: 120 adults with prediabetes (30-70 years, BMI≥25 kg/m2, HbA1c 5.7-6.4%) were randomized to 13 weeks of dapagliflozin (10 mg once daily), metformin (850 mg twice daily), exercise (30 min, 5 days/week) or control (habitual living). Fasting plasma levels of ALT, AST, and GGT were measured at baseline and after 6 and 13 weeks of intervention and after 26 weeks of follow-up. Linear mixed-effects models were performed. Results: At baseline, median (Q1;Q3) HbA1c was 5.9% (5.7; 6.1). 17% had elevated ALT levels, 3% elevated AST levels, and 6% elevated GGT levels. ALT and AST levels did not change in response to the interventions (Table 1). Small within-group changes in GGT were observed in the active groups after 6, 13 or 26 weeks, but they did not differ from the control group (P≥0.09 for all comparisons). Conclusions: 13 weeks of treatment with dapagliflozin, metformin or exercise was not associated with changes in liver function markers compared with habitual living in people with prediabetes. Disclosure M.B. Blond: None. K.K. Clemmensen: Research Support; Self; AstraZeneca, Novo Nordisk Foundation. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. H. Amadid: None. L.B. Nielsen: None. M. Ried-Larsen: None. K. Karstoft: Employee; Spouse/Partner; Novo Nordisk A/S. F. Persson: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Research Support; Self; Amgen, AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. K. Faerch: None. Funding Novo Nordisk Foundation; AstraZeneca; University of Copenhagen; Innovation Foundation

Background: Non-western (non-w) migrants in Europe are at increased risk of type 2 diabetes (T2D) but it is not known if this translates into increased risk of atherosclerotic cardiovascular disease (ASCVD). We calculated age- and sex-specific incidence rates (IR) of ASCVD following T2D among 1st generation migrants in Denmark compared with Danish-born citizens. Methods: Data were obtained from nationwide registers. A total of 346,947 people diagnosed with T2D between 1997-2016 were followed for a median (IQR) of 6.7 (8.8) yr, and classified as Danish-born citizens, western- or non-w migrants according to country of birth. IR of first ASCVD event and death from other causes were estimated separately using Poisson regression with risk time as offset, adjusting for T2D duration and education. Results: Non-w migrants (n=27,693) were younger at T2D diagnosis than Danish-born (mean [SD], 50.8 [11.8] vs. 61.6 [13.5] yr). In total, 104,286 persons (30.1%) developed ASCVD. In adjusted models, ASCVD rates were higher for non-w migrant women at 40-60 yr but lower for both genders at 60-80 yr, compared to western migrants and Danish-born (Figure 1A-B). Non-ASCVD related mortality was also lower among non-w migrants (Figure 1C). Conclusion: Non-w migrants had lower risk of developing ASCVD at 60-80 yr and lower mortality from other causes. This may reflect a ’healthy migrant effect’ or differences in lifestyle or medication. Disclosure G.S. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S. S. Byberg: None. A.D. Bjørkman: None. A.A. Isaksen: Research Support; Self; Novo Nordisk Foundation. H. Amadid: None. B. Carstensen: Stock/Shareholder; Self; Novo Nordisk A/S. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S.

We aimed to investigate the short-term efficacy and safety of three glucose-lowering interventions in overweight or obese individuals with prediabetes defined by HbAThe PRE-D Trial was a randomised, controlled, parallel, multi-arm, open-label, non-blinded trial performed at Steno Diabetes Center Copenhagen, Gentofte, Denmark. One hundred and twenty participants with BMI ≥25 kg/mOne hundred and twelve participants attended the examination at 13 weeks and 111 attended the follow-up visit at 26 weeks. Compared with the control group, there was a small decrease in MAGE in the dapagliflozin group (17.1% [95% CI 0.7, 30.8], p = 0.042) and a small, non-significant, reduction in the exercise group (15.3% [95% CI -1.2, 29.1], p = 0.067), whereas MAGE was unchanged in the metformin group (0.1% [95% CI -16.1, 19.4], p = 0.991)). Compared with the metformin group, MAGE was 17.2% (95% CI 0.8, 30.9; p = 0.041) lower in the dapagliflozin group and 15.4% (95% CI -1.1, 29.1; p = 0.065) lower in the exercise group after 13 weeks, with no difference between exercise and dapagliflozin (2.2% [95% CI -14.8, 22.5], p = 0.815). One serious adverse event occurred in the control group (lung cancer).Treatment with dapagliflozin and interval-based exercise lead to similar but small improvements in glycaemic variability compared with control and metformin therapy. The clinical importance of these findings in prediabetes is uncertain.ClinicalTrials.gov NCT02695810 FUNDING: The study was funded by the Novo Nordisk Foundation, AstraZeneca AB, the Danish Innovation Foundation, the University of Copenhagen and Ascensia Diabetes Care Denmark ApS Graphical abstract.

Purpose Physical activity (PA) is important in the prevention of Type 2 diabetes, yet little is known about the role of specific dimensions of PA, including sedentary time in subgroups at risk for impaired glucose metabolism (IGM). We applied a data-driven decision tool to identify dimensions of PA associated with IGM across age, sex, and body mass index (BMI) groups. Methods This cross-sectional study included 1501 individuals (mean (SD) age, 65.6 (6.8) yr) at high risk for Type 2 diabetes from the ADDITION-PRO study. PA was measured by an individually calibrated combined accelerometer and heart rate monitor worn for 7 d. PA energy expenditure, time spent in different activity intensities, bout duration, and sedentary time were considered determinants of IGM together with age, sex, and BMI. Decision tree analysis was applied to identify subgroup-specific dimensions of PA associated with IGM. IGM was based on oral glucose tolerance test results and defined as a fasting plasma glucose level of ≥6.1 mmol·L-1 and/or a 2-h plasma glucose level of ≥7.8 mmol·L-1. Results Among overweight (BMI ≥25 kg·m-2) men, accumulating less than 30 min·d-1 of moderate-to-vigorous PA was associated with IGM, whereas among overweight women, sedentary time was associated with IGM. Among individuals older than 53 yr with normal weight (BMI -2), time spent in light PA was associated with IGM. None of the dimensions of PA were associated with IGM among individuals ≤53 yr of age with normal weight. Conclusions We identified subgroups in which different activity dimensions were associated with IGM. Methodology and results from this study may suggest a preliminary step toward the goal of tailoring and targeting PA interventions aimed at Type 2 diabetes prevention.

Rationale The hormone glucagon-like peptide-1 (GLP-1) decreases blood glucose and appetite. Greater physical activity (PA) is associated with lower incidence of type 2 diabetes. While acute exercise may increase glucose-induced response of GLP-1, it is unknown how habitual PA affects GLP-1 secretion. We hypothesised that habitual PA associates with greater glucose-induced GLP-1 responses in overweight individuals. Methods Cross-sectional analysis of habitual PA levels and GLP-1 concentrations in 1326 individuals (mean (s.d.) age 66 (7) years, BMI 27.1 (4.5) kg/m2) from the ADDITION-PRO cohort. Fasting and oral glucose-stimulated GLP-1 responses were measured using validated radioimmunoassay. PA was measured using 7-day combined accelerometry and heart rate monitoring. From this, energy expenditure (PAEE; kJ/kg/day) and fractions of time spent in activity intensities (h/day) were calculated. Cardiorespiratory fitness (CRF; mL O2/kg/min) was calculated using step tests. Age-, BMI- and insulin sensitivity-adjusted associations between PA and GLP-1, stratified by sex, were evaluated by linear regression analysis. Results In 703 men, fasting GLP-1 concentrations were 20% lower (95% CI: −33; −3%, P = 0.02) for every hour of moderate-intensity PA performed. Higher CRF and PAEE were associated with 1–2% lower fasting GLP-1 (P = 0.01). For every hour of moderate-intensity PA, the glucose-stimulated GLP-1 response was 16% greater at peak 30 min (1; 33%, P rAUC0-30 = 0.04) and 20% greater at full response (3; 40%, P rAUC0-120 = 0.02). No associations were found in women who performed PA 22 min/day vs 32 min/day for men. Conclusion Moderate-intensity PA is associated with lower fasting and greater glucose-induced GLP-1 responses in overweight men, possibly contributing to improved glucose and appetite regulation with increased habitual PA.

Introduction: We assessed the efficacy of three glucose-lowering interventions in persons with HbA1c-defined prediabetes. Methods: 120 participants were randomised 1:1:1:1 to 13 weeks of 1) dapagliflozin (DAP, 10 m/day); 2) metformin (MET, 1700 mg/day); 3) exercise (EXE, 5 x 30 min/week); or 4) control (CON, no treatment). Continuous glucose monitor (CGM) was used for 6 days before, during (6 weeks) and after (13 weeks) the intervention. Treatments were stopped the day before the last visit (two days before in EXE). Primary outcome was 13-week change in mean amplitude of glycaemic excursions (MAGE). Intention-to-treat analysis was conducted. Results: At baseline, median (Q1;Q3) HbA1c was 5.9 (5.7;6.1)%; BMI 30.8 (28.6;34.3) kg/m2; age 62 (54;68) years; 44% were men. No within- or between-group changes were observed for MAGE. Mean CGM glucose (MG) was slightly reduced in MET and DAP at 6 weeks (Table 1). The 6-week change in MG in DAP was different from that in CON (mean diff. (95% CI): -0.3 mM (-0.5;0.0), P=0.031). At 13 weeks, MG had increased in MET and CON, and the change in MET was different from those in EXE (0.2 mM (0.0;0.5), P=0.041) and DAP (0.2 mM (0.0;0.5), P=0.039). Conclusion: 13 weeks of treatment with MET, DAP or EXE did not change MAGE. Treatment with DAP or MET for 6 weeks slightly reduced MG; these improvements disappeared immediately after treatments were stopped at 13 weeks. Disclosure K. Færch: Research Support; Self; Ascensia Diabetes Care, AstraZeneca, Unilever. Stock/Shareholder; Self; Novo Nordisk A/S. D. Vistisen: Stock/Shareholder; Self; Novo Nordisk A/S. M.B. Blond: None. L.B. Nielsen: None. H. Amadid: None. T.F. Dejgaard: Consultant; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Boehringer Ingelheim International GmbH. M. Ried-Larsen: Other Relationship; Self; Novo Nordisk A/S. K. Karstoft: Employee; Self; Novo Nordisk A/S. F. Persson: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. M.E. Jørgensen: Research Support; Self; Amgen Inc., AstraZeneca, Danish Diabetes Association, Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. Funding Novo Nordisk Foundation; AstraZeneca

Introduction: Safety, adherence and treatment satisfaction to interventions with dapagliflozin, metformin or exercise in individuals with prediabetes defined by the HbA1c criterion were studied in the randomized controlled PRE-D trial. Methods: 120 participants were randomized 1:1:1:1 to 13 weeks of either: (1) dapagliflozin (DAP, 10 mg daily); (2) metformin (MET, 1700 mg daily); (3) exercise (EXE, 5x30 min/week); or (4) control (CON, no treatment). Adverse events (AE) were collected during the entire study. Satisfaction with the interventions was assessed at 6 and 13 weeks using questionnaires. Adherence was assessed at 6 and 13 weeks by pill count in DAP and MET and each week by uploaded training data in EXE. Comparisons between groups were performed by ANOVA and chi-square tests. Results: At baseline, the median (Q1;Q3) HbA1c was 41 (39;43) mmol/mol (5.9 (5.7;6.1)%); age 62 (54;68) years, and 44% were men. Drop outs were 2 in DAP, 1 in MET, 3 in EXE and 2 in CON. One serious AE occurred in CON (cancer). 40% of the participants experienced at least one AE during the trial (15 in DAP, 22 in MET, 7 in EXE and 4 in CON (DAP vs. MET: P=0.111; MET vs. EXE: P Conclusion: In individuals with prediabetes, treatment with DAP is safe and did not result in more side-effects than treatment with MET. Adherence to all interventions was high, although the most preferred intervention was the EXE intervention. Disclosure H. Amadid: None. M.B. Blond: None. L. Bruhn: None. K.K. Clemmensen: None. C.T. Vainø: None. F. Persson: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. M.E. Jørgensen: Research Support; Self; Amgen Inc., AstraZeneca, Danish Diabetes Association, Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. K. Færch: Research Support; Self; Ascensia Diabetes Care, AstraZeneca, Unilever. Stock/Shareholder; Self; Novo Nordisk A/S.

Introduction: We assessed the effects of dapagliflozin, metformin or exercise on glucose metabolism in individuals with prediabetes. Methods: 120 participants were randomized to 13 weeks of either: 1) dapagliflozin (DAP, 10 mg once daily); 2) metformin (MET, 1700 mg daily); 3) exercise (EXE, 5x30 min/week); or 4) control (CON, no treatment). Participants were tested at baseline and after 6 and 13 weeks of intervention with oral glucose tolerance tests with 0, 30, 60, 120 min samples performed at baseline and at 13 weeks. Treatments were stopped the day before the last visit (two days before in EXE). Intention-to-treat analyses were conducted (baseline-adjusted). Results: 44% were men. At baseline, the median (Q1;Q3) age was 62 (54;68) years, BMI 30.8 (28.6;34.3) kg/m2, HbA1c 41 (39;43) mmol/mol (5.9 (5.7;6.1)%), fasting plasma glucose (FPG) 5.6 (5.2;5.8) mmol/L, and fasting serum insulin (FSI) 72 (47;99) pmol/L. HbA1c decreased in DAP at 6 weeks (Table 1). All groups showed reductions of around 1 mmol/mol at 13 weeks. MET, and to a lesser extend DAP, decreased FPG. FSI was reduced by 19-25% in all treatment groups, except for EXE at 13 weeks. The iAUCglucose increased by 66% in MET, and iAUCinsulin decreased somewhat in DAP and EXE. Conclusion: All treatments slightly improved HbA1c and fasting measures. Only DAP and EXE showed signs of improvements in postprandial glucose metabolism. Disclosure K. Færch: Research Support; Self; Ascensia Diabetes Care, AstraZeneca, Unilever. Stock/Shareholder; Self; Novo Nordisk A/S. M.B. Blond: None. H. Amadid: None. L.B. Nielsen: None. D. Vistisen: Stock/Shareholder; Self; Novo Nordisk A/S. K.K. Clemmensen: None. C.H. Pedersen: None. K. Karstoft: Employee; Self; Novo Nordisk A/S. M. Ried-Larsen: Other Relationship; Self; Novo Nordisk A/S. M.E. Jørgensen: Research Support; Self; Amgen Inc., AstraZeneca, Danish Diabetes Association, Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. Funding Novo Nordisk Foundation; AstraZeneca

Background Ambiguity exists in relation to the role of physical activity (PA) for cardiovascular disease (CVD) risk reduction. We examined the interplay between PA dimensions and more conventional CVD risk factors to assess which PA dimensions were associated with the first CVD event and whether subgroup differences exist. Methods A total of 1449 individuals [median age 65.8 (IQR: 61.2, 70.7) years] with low to high risk of type 2 diabetes and free from CVD from the Danish ADDITION-PRO study were included for survival analysis. PA was measured by individually calibrated heart rate and movement sensing for 7 consecutive days. The associations of different PA dimensions (PA energy expenditure, time spent in light-, moderate- and vigorous intensity PA), sedentary time and other conventional CVD risk factors with the first CVD event were examined by tree-structured survival analysis. Baseline information was linked to data on the first CVD event (ischemic heart disease, ischemic stroke, heart failure, atrial flutter/fibrillation and atherosclerotic disease) and mortality obtained from Danish registers. Results During a median follow-up time of 5.5 (IQR: 5.1–6.1) years, a total of 201 individuals (13.9%) developed CVD. Overall CVD incidence rate was 2.6/100 person-years. PA energy expenditure above 43 kJ/kg/day was associated with lower rates of CVD events among participants ≤ 70 years and with HbA1c ≤ 5.7% (39 mmol/mol), systolic blood pressure ≤ 156 mmHg and albumin creatinine ratio ≤ 70 (incidence rates 0.0–0.8/100 person-years). Conclusions Any type of PA resulting in increased PA energy expenditure may over time be the best prevention strategy to uphold reduced risk of CVD. Electronic supplementary material The online version of this article (10.1186/s12933-018-0769-x) contains supplementary material, which is available to authorized users.

INTRODUCTION: The primary aim of this study is to compare the efficacy of three short-term glucose-lowering interventions (exercise, metformin and dapagliflozin) on glycaemic variability in overweight or obese men and women with elevated diabetes risk (ie, prediabetes, defined as haemoglobin A1c (HbA1c)39-47 mmol/mol / 5.7%-6.4%). The secondary aims are to investigate the effects of the interventions on body composition and cardiometabolic risk factors.METHODS AND ANALYSIS: The Pre-D Trial is an investigator-initiated, randomised, controlled, parallel, open-label, superiority trial. The study aims to assign 120 participants in a 1:1:1:1 ratio to receive one of four interventions for 13 weeks: (1) dapagliflozin (10 mg once daily); (2) metformin (850 mg twice daily); (3) exercise (interval training, 5 days a week, 30 min per session); or (4) control (lifestyle advice). After the 13 weeks of intervention, a follow-up period of 13 weeks will follow to study the long-term effects of the interventions. The primary endpoint is reduction from baseline to end-of treatment (13 weeks) in mean amplitude of glycaemic excursions measured by continuous glucose monitoring. The secondary endpoints include concomitant changes in various measures of glucose metabolism, body weight, cardiorespiratory fitness, blood pressure, plasma lipids, objectively measured physical activity and dietary intake.ETHICS AND DISSEMINATION: The study protocol has been approved by the Ethics Committee of the Capital Region and the Danish Medicines Agency. Approval of data and biobank storage has been obtained from the Danish Data Protection Board. The study will be carried out according to the Declaration of Helsinki and to the regulations for good clinical practice. The results from this trial will allow a number of research questions concerning the effect of exercise versus dapagliflozin or metformin in HbA1c-defined prediabetes to be addressed.TRIAL REGISTRATION: NCT02695810.