Why prescribe exercise as therapy in type 2 diabetes? We have a pill for that!

The majority of T2D cases are preventable through a healthy lifestyle, leaving little room for questions that lifestyle should be the first line of defence in the fight against the development of T2D. However, when it comes to the clinical care of T2D, the potential efficacy of lifestyle is much less clear-cut, both in terms of impacting the pathological metabolic biomarkers of the disease, and long-term complications. A healthy diet, high leisure-time physical activity, and exercise are considered to be cornerstones albeit adjunct to drug therapy in the management of T2D. The prescription and effective implementation of structured exercise and other lifestyle interventions in the treatment of T2D have not been routinely used. In this article, we critically appraise and debate our reflections as to why exercise and physical activity may not have reached the status of a viable and effective treatment in the clinical care of T2D to the same extent as pharmaceutical drugs. We argue that the reason why exercise therapy is not utilized to a satisfactory degree is multifaceted and primarily relates to a "vicious cycle" with lack of proven efficacy on T2D complications and a lack of proven effectiveness on risk factors in the primary care of T2D. Furthermore, there is a lack of experimental research establishing the optimal dose of exercise. This precludes widespread and sustained implementation of physical activity and exercise in the clinical treatment of T2D will not succeed.

Time trends in mortality rates in type 1 diabetes from 2002 to 2011.

AIMS/HYPOTHESIS: The aim of this study was to estimate absolute and relative mortality rates in patients with type 1 diabetes at the Steno Diabetes Centre relative to the general Danish background population. METHODS: Patients with type 1 diabetes (n = 4,821) were followed from 1 January 2002 until 1 January 2011, with death from any cause as the main outcome. Poisson regression was used to model mortality rates by age, diabetes duration and calendar time, according to sex. RESULTS: In the period 2002-2010, a total of 673 deaths (402 men, 271 women) occurred in the study population during 33,847 years of follow-up of type 1 diabetes. The predominant cause of death in patients with type 1 diabetes was cardiovascular disease. Mortality rates were highest among those with the lowest age at onset, particularly men. The mortality rate in the diabetic population decreased over that time period by 6.6% and 4.8% per year in men and women, respectively; this was substantially greater than the decrease in mortality rates in the background population. The decline in standard mortality rate was 4.3% per year in men and 2.6% per year in women. Patients who did not develop nephropathy had only slightly elevated mortality rates compared with the background population. CONCLUSIONS/INTERPRETATION: Despite advances in care, mortality rates in the past decade continue to be greater in patients with type 1 diabetes than in those without diabetes; however, the mortality rate in patients decreased over the study period faster than that of the background population. Nephropathy seems to be the main driver of the excess mortality.

Soluble urokinase plasminogen activator receptor, C-reactive protein and triglyceride are associated with heart rate variability in non-diabetic Danes.

BACKGROUND: Heart rate variability (HRV) is associated with an increased risk of cardiovascular morbidity and mortality. HRV is in part a function of the activity of the autonomic nervous system and has been associated with low-grade inflammation. In patients with type 2 diabetes, HRV is decreased and is a predictor of poor outcome. As HRV and its determinants in non-diabetic individuals have not been studied properly, the aim of this observational study was to evaluate possible associations between HRV vs. impaired fasting glucose, insulin resistance, lipidaemia and markers of inflammation and immune activation in these individuals. MATERIALS AND METHODS: Healthy individuals (n = 596, 55-75 years) from the community were evaluated with ambulant 48-h continuous electrocardiogram monitoring and fasting markers of lipidaemia, inflammation and immune activation, respectively. Insulin resistance was estimated by HOMA-IR. Time domain components of HRV were calculated. RESULTS: Heart rate and HRV were not associated with glucose metabolic parameters but were inversely associated with soluble urokinase plasminogen activator receptor (suPAR), high-sensitive CRP and leucocyte number (P < 0·001), respectively. Both 24-h and night-time HRV were inversely associated with plasma triglyceride, whereas HDL, LDL and total cholesterol were not. A model including suPAR, CRP, gender, triglyceride, age, systolic blood pressure, physical activity and smoking status explained 12·2% (P < 0·0001) of the 24-h HRV and 7·3% (P < 0·0001) of the night-time HRV. The single strongest factor to explain 24-h and night-time HRV appeared to be suPAR (P = 0·001 and P = 0·0067, respectively). CONCLUSION: A low HRV is not related to prediabetes, that is, insulin resistance and impaired fasting glucose, but is related to the immune and inflammatory markers suPAR and CRP and plasma triglyceride.

Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus.

BACKGROUND: Patients with type 2 diabetes mellitus (T2D) have an increased risk of cardiovascular disease and mortality compared to the background population. Observational studies report an association between reduced blood glucose and reduced risk of both micro- and macrovascular complications in patients with T2D. Our previous systematic review of intensive glycaemic control versus conventional glycaemic control was based on 20 randomised clinical trials that randomised 29 ,986 participants with T2D. We now report our updated review. OBJECTIVES: To assess the effects of targeted intensive glycaemic control compared with conventional glycaemic control in patients with T2D. SEARCH METHODS: Trials were obtained from searches of The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL (all until December 2012). SELECTION CRITERIA: We included randomised clinical trials that prespecified targets of intensive glycaemic control versus conventional glycaemic control targets in adults with T2D. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias and extracted data. Dichotomous outcomes were assessed by risk ratios (RR) and 95% confidence intervals (CI). Health-related quality of life and costs of intervention were assessed with standardized mean differences (SMD) and 95% Cl. MAIN RESULTS: Twenty-eight trials with 34,912 T2D participants randomised 18,717 participants to intensive glycaemic control versus 16,195 participants to conventional glycaemic control. Only two trials had low risk of bias on all risk of bias domains assessed. The duration of the intervention ranged from three days to 12.5 years. The number of participants in the included trials ranged from 20 to 11,140. There were no statistically significant differences between targeting intensive versus conventional glycaemic control for all-cause mortality (RR 1.00, 95% CI 0.92 to 1.08; 34,325 participants, 24 trials) or cardiovascular mortality (RR 1.06, 95% CI 0.94 to 1.21; 34,177 participants, 22 trials). Trial sequential analysis showed that a 10% relative risk reduction could be refuted for all-cause mortality. Targeting intensive glycaemic control did not show a statistically significant effect on the risks of macrovascular complications as a composite outcome in the random-effects model, but decreased the risks in the fixed-effect model (random RR 0.91, 95% CI 0.82 to 1.02; and fixed RR 0.93, 95% CI 0.87 to 0.99; P = 0.02; 32,846 participants, 14 trials). Targeting intensive versus conventional glycaemic control seemed to reduce the risks of non-fatal myocardial infarction (RR 0.87, 95% CI 0.77 to 0.98; P = 0.02; 30,417 participants, 14 trials), amputation of a lower extremity (RR 0.65, 95% CI 0.45 to 0.94; P = 0.02; 11,200 participants, 11 trials), as well as the risk of developing a composite outcome of microvascular diseases (RR 0.88, 95% CI 0.82 to 0.95; P = 0.0008; 25,927 participants, 6 trials), nephropathy (RR 0.75, 95% CI 0.59 to 0.95; P = 0.02; 28,096 participants, 11 trials), retinopathy (RR 0.79, 95% CI 0.68 to 0.92; P = 0.002; 10,300 participants, 9 trials), and the risk of retinal photocoagulation (RR 0.77, 95% CI 0.61 to 0.97; P = 0.03; 11,212 participants, 8 trials). No statistically significant effect of targeting intensive glucose control could be shown on non-fatal stroke, cardiac revascularization, or peripheral revascularization. Trial sequential analyses did not confirm a reduction of the risk of non-fatal myocardial infarction but confirmed a 10% relative risk reduction in favour of intensive glycaemic control on the composite outcome of microvascular diseases. For the remaining microvascular outcomes, trial sequential analyses could not establish firm evidence for a 10% relative risk reduction. Targeting intensive glycaemic control significantly increased the risk of mild hypoglycaemia, but substantial heterogeneity was present; severe hypoglycaemia (RR 2.18, 95% CI 1.53 to 3.11; 28,794 participants, 12 trials); and serious adverse events (RR 1.06, 95% CI 1.02 to 1.10; P = 0.007; 24,280 participants, 11 trials). Trial sequential analysis for a 10% relative risk increase showed firm evidence for mild hypoglycaemia and serious adverse events and a 30% relative risk increase for severe hypoglycaemia when targeting intensive versus conventional glycaemic control. Overall health-related quality of life, as well as the mental and the physical components of health-related quality of life did not show any statistical significant differences. AUTHORS' CONCLUSIONS: Although we have been able to expand the number of participants by 16% in this update, we still find paucity of data on outcomes and the bias risk of the trials was mostly considered high. Targeting intensive glycaemic control compared with conventional glycaemic control did not show significant differences for all-cause mortality and cardiovascular mortality. Targeting intensive glycaemic control seemed to reduce the risk of microvascular complications, if we disregard the risks of bias, but increases the risk of hypoglycaemia and serious adverse events.

Quality of life, patient satisfaction, and cardiovascular outcomes of the randomised 2 x 3 factorial Copenhagen insulin and Metformin therapy (CIMT) trial - A detailed statistical analysis plan.

Background: The evidence on the effects of metformin and insulin in type 2 diabetes patients on quality of life, patient satisfaction, and cardiovascular outcomes is unclear. Methods: The Copenhagen Insulin and Metformin Therapy (CIMT) trial is an investigator-initiated multicentre, randomised, placebo-controlled trial with a 2 × 3 factorial design conducted at eight hospitals in Denmark. Participants with type 2 diabetes were randomised to metformin (n = 206) versus placebo (n = 206); in combination with open-label biphasic insulin aspart one to three times daily (n = 137) versus insulin aspart three times daily in combination with insulin detemir once daily (n = 138) versus insulin detemir once daily (n = 137).We present a detailed description of the methodology and statistical analysis of the clinical CIMT outcomes including a detailed description of tests of the assumptions behind the statistical analyses. The outcomes are quality of life (Short Form Health Survey (SF-36)), Diabetes Medication Satisfaction Questionnaire, and Insulin Treatment Satisfaction Questionnaire (assessed at entry and 18 months after randomisation) and cardiovascular outcomes including time to a composite of either myocardial infarction, stroke, peripheral amputation, coronary revascularisation, peripheral revascularisation, or death. Discussions: This statistical analysis plan ensure the highest possible quality of the subsequent post-hoc analyses. Trial registration: The protocol was approved by the Regional Committee on Biomedical Research Ethics (H-D-2007-112), the Danish Medicines Agency (EudraCT: 2007-006665-33 CIMT), and registered within ClinicalTrials.gov (NCT00657943, 8th of April 2008).

Effects of different doses of exercise and diet-induced weight loss on beta-cell function in type 2 diabetes (DOSE-EX): a randomized clinical trial.

Diet-induced weight loss is associated with improved beta-cell function in people with type 2 diabetes (T2D) with remaining secretory capacity. It is unknown if adding exercise to diet-induced weight loss improves beta-cell function and if exercise volume is important for improving beta-cell function in this context. Here, we carried out a four-armed randomized trial with a total of 82 persons (35% females, mean age (s.d.) of 58.2 years (9.8)) with newly diagnosed T2D (<7 years). Participants were randomly allocated to standard care (n = 20), calorie restriction (25% energy reduction; n = 21), calorie restriction and exercise three times per week (n = 20), or calorie restriction and exercise six times per week (n = 21) for 16 weeks. The primary outcome was beta-cell function as indicated by the late-phase disposition index (insulin secretion multiplied by insulin sensitivity) at steady-state hyperglycemia during a hyperglycemic clamp. Secondary outcomes included glucose-stimulated insulin secretion and sensitivity as well as the disposition, insulin sensitivity, and secretion indices derived from a liquid mixed meal tolerance test. We show that the late-phase disposition index during the clamp increases more in all three intervention groups than in standard care (diet control group, 58%; 95% confidence interval (CI), 16 to 116; moderate exercise dose group, 105%; 95% CI, 49 to 182; high exercise dose group, 137%; 95% CI, 73 to 225) and follows a linear dose-response relationship (P > 0.001 for trend). We report three serious adverse events (two in the control group and one in the diet control group), as well as adverse events in two participants in the diet control group, and five participants each in the moderate and high exercise dose groups. Overall, adding an exercise intervention to diet-induced weight loss improves glucose-stimulated beta-cell function in people with newly diagnosed T2D in an exercise dose-dependent manner (NCT03769883).

Glucometabolic changes influence hospitalization and outcome in patients with COVID-19: An observational cohort study.

AIMS: The aim was to report the prevalence of diabetes status in patients hospitalized with COVID-19 and assess the association between the glucometabolic status at admission and 90-day mortality. METHODS: Consecutive patients hospitalized with COVID-19 were included in the study. All participants included had an HbA1c measurement 60 days prior to or within 7 days after admission. We studied the association between diabetes status, the glycemic gap (difference between admission and habitual status), admission plasma-glucose, and mortality using Cox proportional hazards regression. RESULTS: Of 674 patients included, 114 (17%) had normal glucose level, 287 (43%) had pre-diabetes, 74 (11%) had new-onset, and 199 (30%) had diagnosed diabetes. No association between diabetes status, plasma-glucose at admission, and mortality was found. Compared to the 2nd quartile (reference) of glycemic-gap, those with the highest glycemic gap had increased mortality (3rd (HR 2.38 [1.29-4.38], p = 0.005) and 4th quartile (HR 2.48 [1.37-4.52], p = 0.002). CONCLUSION: Abnormal glucose metabolism was highly prevalent among patients hospitalized with COVID-19. Diabetes status per se or admission plasma-glucose was not associated with a poorer outcome. However, a high glycemic gap was associated with increased risk of mortality, suggesting that, irrespective of diabetes status, glycemic stress serves as an important prognostic marker for mortality.

Effects of an exercise-based lifestyle intervention on systemic markers of oxidative stress and advanced glycation endproducts in persons with type 2 diabetes: Secondary analysis of a randomised clinical trial.

AIMS/HYPOTHESIS: This secondary analysis aimed to investigate the effects of a 12 months intensive exercise-based lifestyle intervention on systemic markers of oxidative stress in persons with type 2 diabetes. We hypothesized lifestyle intervention to be superior to standard care in decreasing levels of oxidative stress. METHODS: The study was based on the single-centre, assessor-blinded, randomised, controlled U-turn trial (ClinicalTrial.gov NCT02417012). Persons with type 2 diabetes ˂ 10 years, ˂ 3 glucose lowering medications, no use of insulin, BMI 25-40 kg/m2 and no severe diabetic complications were included. Participants were randomised (2:1) to either intensive exercise-based lifestyle intervention and standard (n = 64) or standard care alone (n = 34). Standard care included individual education in diabetes management, advice on a healthy lifestyle and regulation of medication by a blinded endocrinologist. The lifestyle intervention included five to six aerobic exercise sessions per week, combined with resistance training two to three times per week and an adjunct dietary intervention aiming at reduction of ∼500 kcal/day (month 0-4). The diet was isocaloric from months 5-12. The primary outcome of this secondary analysis was change in oxidative stress measured by 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and secondarily in 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), as markers of RNA and DNA oxidation, respectively, from baseline to 12-months follow-up. RESULTS: A total of 77 participants, 21 participants receiving standard care and 56 participants receiving the lifestyle intervention, were included in the analysis. Mean age at baseline was 54.1 years (SD 9.1), 41% were women and mean duration of type 2 diabetes was 5.0 years (SD 2.8). From baseline to follow-up the lifestyle group experienced a 7% decrease in 8-oxoGuo (-0.15 nmol/mmol creatinine [95% CI -0.27, -0.03]), whereas standard care conversely was associated with a 8.5% increase in 8-oxoGuo (0.19 nmol/mmol creatinine [95% CI 0.00, 0.40]). The between group difference in 8-oxoGuo was -0.35 nmol/mmol creatinine [95% CI -0.58, -0.12,], p = 0.003. No between group difference was observed in 8-oxodG. CONCLUSION/INTERPRETATION: A 12 months intensive exercise-based lifestyle intervention was associated with a decrease in RNA, but not DNA, oxidation in persons with type 2 diabetes.

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.

The effects of different doses of exercise on pancreatic ß-cell function in patients with newly diagnosed type 2 diabetes: study protocol for and rationale behind the "DOSE-EX" multi-arm parallel-group randomised clinical trial.

BACKGROUND: Lifestyle intervention, i.e. diet and physical activity, forms the basis for care of type 2 diabetes (T2D). The current physical activity recommendation for T2D is aerobic training for 150 min/week of moderate to vigorous intensity, supplemented with resistance training 2-3 days/week, with no more than two consecutive days without physical activity. The rationale for the recommendations is based on studies showing a reduction in glycated haemoglobin (HbA1c). This reduction is supposed to be caused by increased insulin sensitivity in muscle and adipose tissue, whereas knowledge about effects on abnormalities in the liver and pancreas are scarce, with the majority of evidence stemming from in vitro and animal studies. The aim of this study is to investigate the role of the volume of exercise training as an adjunct to dietary therapy in order to improve the pancreatic ß-cell function in T2D patients less than 7 years from diagnosis. The objective of this protocol for the DOSE-EX trial is to describe the scientific rationale in detail and to provide explicit information about study procedures and planned analyses. METHODS/DESIGN: In a parallel-group, 4-arm assessor-blinded randomised clinical trial, 80 patients with T2D will be randomly allocated (1:1:1:1, stratified by sex) to 16 weeks in either of the following groups: (1) no intervention (CON), (2) dietary intervention (DCON), (3) dietary intervention and supervised moderate volume exercise (MED), or (4) dietary intervention and supervised high volume exercise (HED). Enrolment was initiated December 15th, 2018, and will continue until N = 80 or December 1st, 2021. Primary outcome is pancreatic beta-cell function assessed as change in late-phase disposition index (DI) from baseline to follow-up assessed by hyperglycaemic clamp. Secondary outcomes include measures of cardiometabolic risk factors and the effect on subsequent complications related to T2D. The study was approved by The Scientific Ethical Committee at the Capital Region of Denmark (H-18038298). TRIAL REGISTRATION: The Effects of Different Doses of Exercise on Pancreatic ß-cell Function in Patients With Newly Diagnosed Type 2 Diabetes (DOSE-EX), NCT03769883, registered 10 December 2018 https://clinicaltrials.gov/ct2/show/NCT03769883 ). Any modification to the protocol, study design, and changes in written participant information will be approved by The Scientific Ethical Committee at the Capital Region of Denmark before effectuation. DISCUSSION: The data from this study will add knowledge to which volume of exercise training in combination with a dietary intervention is needed to improve ß-cell function in T2D. Secondarily, our results will elucidate mechanisms of physical activity mitigating the development of micro- and macrovascular complications correlated with T2D.

Carotid intima-media thickness in individuals with and without type 2 diabetes: a reproducibility study.

BACKGROUND: The use of carotid intima-media thickness (carotid IMT) as a surrogate marker of cardiovascular disease is increasing and the method has now also been applied in several trials investigating patients with type 2 diabetes (T2D). Even though knowledge about methodology is of highest importance in order to make accurate power calculations and analyses of results, no reproducibility studies have been performed in this group of patients. The aim of this study was to quantify the variability of the measurement of carotid IMT in individuals with and without T2D. METHODS: We used B-mode ultrasound and a computerized software programme (MIA vascular tools) for analysis of carotid IMT. Measurement of carotid IMT in the far wall of the common carotid artery (CCA) was done for 30 patients with T2D and 30 persons without T2D. The examinations were done by two different sonographers and two different readers on two separate days in order to quantify sonographer-, reader-, and day-to-day variability. RESULTS: Comparisons of measurement of carotid IMT in CCA between sonographers (sonographer variability) resulted in limits of agreement (LoA) from -0.18 to 0.13 mm for patients with T2D and -0.12 to 0.10 mm for persons without T2D. This means, that a second scanning of the same person with 95% probability would be within this interval of the first scanning. Comparisons between readers assessing the same scanning (reader variability) resulted in LoA from -0.05 to 0.07 mm and -0.04 to 0.05 mm respectively. LoA of the day-to-day variability was -0.13 to 0.18 mm and -0.09 to 0.18 mm respectively. This corresponds to coefficients of variations (CV) of the sonographer- and day-to-day variability of 10% in patients with T2D and 8% in persons without T2D. The CV of the reader variability was 4% and 3% respectively. CONCLUSION: Measurement of carotid IMT in the CCA can be determined with good and comparable reproducibility in both patients with T2D and persons without T2D. These findings support the use of carotid IMT in clinical trials with T2D patients and suggest that the numbers of patients needed to detect a given difference will be the same whether the patients have T2D or not.

Study protocol for optimising glycaemic control in type 1 diabetes treated with multiple daily insulin injections: intermittently scanned continuous glucose monitoring, carbohydrate counting with automated bolus calculation, or both? A randomised controlled trial.

INTRODUCTION: There are beneficial effects of advanced carbohydrate counting with an automatic bolus calculator (ABC) and intermittently scanned continuous glucose monitoring (isCGM) in persons with type 1 diabetes. We aim to compare the effects of isCGM, training in carbohydrate counting with ABC and the combination of the two concepts with standard care. METHODS AND ANALYSIS: A multi-centre randomised controlled trial with inclusion criteria: ≥18 years, type 1 diabetes ≥1 year, injection therapy, HbA1c >53 mmol/mol, whereas daily use of carbohydrate counting and/or CGM/isCGM wear are exclusion criteria. Inclusion was initiated in October 2018 and is ongoing. Eligible persons are randomised into four groups: standard care, ABC, isCGM or ABC+isCGM. Devices used are FreeStyle Libre Flash and smart phone diabetes application mySugr. Participants attend group courses according to treatment allocation with different educational contents. Participants are followed for 26 weeks with clinical visits and telephone consultations. At baseline and at study end, participants wear blinded CGM, have blood samples performed and fill in questionnaires on person-related outcomes, and at baseline also on personality traits and hypoglycaemia awareness. The primary outcome is the difference in time spent in normoglycaemia (4-10 mmol/L) at study end versus baseline between the isCGM group and the standard care group. Secondary outcomes will also be analysed. Results are expected in 2020. ETHICS AND DISSEMINATION: Regional Scientific Ethics Committee approval (H-17040573). Results will be sought disseminated at conferences and in high impact journals.Trial registration numberClinicalTrial.gov registry (NCT03682237).

Prediction of carotid intima-media thickness and its relation to cardiovascular events in persons with type 2 diabetes.

AIMS: To investigate measures of carotid intima-media thickness (IMT) and conventional cardiovascular (CV) risk factors as predictors of future carotid IMT, and the prediction of CV events during follow-up based on measures of carotid IMT. METHODS: Observational longitudinal study including 230 persons with type 2 diabetes (T2D). RESULTS: Mean age at follow-up was 66.7 (SD 8.5) years, 30.5% were women and mean body mass index (BMI) was 31.8 (4.4) kg/m2. Carotid IMT was measured at baseline, after 18 months of intervention in the Copenhagen Insulin and Metformin Therapy (CIMT) trial and after a mean follow-up of 6.4 (1.0) years. Baseline carotid IMT, carotid IMT after 18 months' intervention, and CV risk factors (age, sex and baseline systolic blood pressure) gave the best prediction of carotid IMT (root mean-squared error of prediction of 0.106 and 95% prediction error probability interval of -0.160, 0.204). CONCLUSIONS: Measures of carotid IMT combined with CV risk factors at baseline predicts attained carotid IMT better than measures of carotid IMT or CV risk factors alone. Carotid IMT did not predict CV events, and the present results do not support the use of carotid IMT as a predictor of CV events in persons with T2D.

Associations between patient characteristics, social relations, diabetes management, quality of life, glycaemic control and emotional burden in type 1 diabetes.

AIM: The objective was to investigate associations between emotional burden and a number of individual variables: patient characteristics, social relations, diabetes management in everyday life, generic quality of life and glycaemic control, including determining to what extend these variables explain the differences in emotional burden in a large Danish population of people with type 1 diabetes. METHODS: We analysed a cross-sectional survey of 2419 Danish adults with type-1 diabetes mellitus and data from an electronic patient record. Data were analysed using hierarchical regression of factors of interest with emotional burden of diabetes as the dependent variable. RESULTS: High emotional burden of diabetes was associated with being female, younger age, other chronic illness, low diabetes-specific support, low generic quality of life, low diabetes empowerment and high Hba1c. Low diabetes empowerment, low generic quality of life and low diabetes-specific support were associated with the largest difference in emotional burden level. CONCLUSIONS: A variety of psychosocial and behavioural factors such as low social support, low generic quality of life and difficulties in managing diabetes are associated with high emotional burden in type-1 diabetes. These findings may call for an expansion of the effort to decrease the emotional burden of diabetes for those who are heavily burdened. Future research should explore the causality of the explored associations as well as potential subgroup differences in order to guide the development of appropriate interventions.

Metformin versus placebo in combination with insulin analogues in patients with type 2 diabetes mellitus-the randomised, blinded Copenhagen Insulin and Metformin Therapy (CIMT) trial.

OBJECTIVE: To assess the effect of metformin versus placebo both in combination with insulin analogue treatment on changes in carotid intima-media thickness (IMT) in patients with type 2 diabetes. DESIGN AND SETTING: Investigator-initiated, randomised, placebo-controlled trial with a 2 × 3 factorial design conducted at eight hospitals in Denmark. PARTICIPANTS AND INTERVENTIONS: 412 participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥ 7.5% (≥ 58 mmol/mol); body mass index >25 kg/m2) were in addition to open-labelled insulin treatment randomly assigned 1:1 to 18 months blinded metformin (1 g twice daily) versus placebo, aiming at an HbA1c ≤ 7.0% (≤ 53 mmol/mol). OUTCOMES: The primary outcome was change in the mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight and hypoglycaemic and serious adverse events were other prespecified outcomes. RESULTS: Change in the mean carotid IMT did not differ significantly between the groups (between-group difference 0.012 mm (95% CI -0.003 to 0.026), p=0.11). HbA1c was more reduced in the metformin group (between-group difference -0.42% (95% CI -0.62% to -0.23%), p<0.001)), despite the significantly lower insulin dose at end of trial in the metformin group (1.04 IU/kg (95% CI 0.94 to 1.15)) compared with placebo (1.36 IU/kg (95% CI 1.23 to 1.51), p<0.001). The metformin group gained less weight (between-group difference -2.6 kg (95% CI -3.3 to -1.8), p<0.001). The groups did not differ with regard to number of patients with severe or non-severe hypoglycaemic or other serious adverse events, but the metformin group had more non-severe hypoglycaemic episodes (4347 vs 3161, p<0.001). CONCLUSIONS: Metformin in combination with insulin did not reduce carotid IMT despite larger reduction in HbA1c, less weight gain, and smaller insulin dose compared with placebo plus insulin. However, the trial only reached 46% of the planned sample size and lack of power may therefore have affected our results. TRIAL REGISTRATION NUMBER: NCT00657943; Results.

Effects of biphasic, basal-bolus or basal insulin analogue treatments on carotid intima-media thickness in patients with type 2 diabetes mellitus: the randomised Copenhagen Insulin and Metformin Therapy (CIMT) trial.

OBJECTIVE: To assess the effect of 3 insulin analogue regimens on change in carotid intima-media thickness (IMT) in patients with type 2 diabetes. DESIGN AND SETTING: Investigator-initiated, randomised, placebo-controlled trial with a 2 × 3 factorial design, conducted at 8 hospitals in Denmark. PARTICIPANTS AND INTERVENTIONS: Participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥ 7.5% (≥ 58 mmol/mol), body mass index >25 kg/m(2)) were, in addition to metformin versus placebo, randomised to 18 months open-label biphasic insulin aspart 1-3 times daily (n=137) versus insulin aspart 3 times daily in combination with insulin detemir once daily (n=138) versus insulin detemir alone once daily (n=137), aiming at HbA1c ≤ 7.0% (≤ 53 mmol/mol). OUTCOMES: Primary outcome was change in mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight, and hypoglycaemic and serious adverse events were other prespecified outcomes. RESULTS: Carotid IMT change did not differ between groups (biphasic -0.009 mm (95% CI -0.022 to 0.004), aspart+detemir 0.000 mm (95% CI -0.013 to 0.013), detemir -0.012 mm (95% CI -0.025 to 0.000)). HbA1c was more reduced with biphasic (-1.0% (95% CI -1.2 to -0.8)) compared with the aspart+detemir (-0.4% (95% CI -0.6 to -0.3)) and detemir (-0.3% (95% CI -0.4 to -0.1)) groups (p<0.001). Weight gain was higher in the biphasic (3.3 kg (95% CI 2.7 to 4.0) and aspart+detemir (3.2 kg (95% CI 2.6 to 3.9)) compared with the detemir group (1.9 kg (95% CI 1.3 to 2.6)). Insulin dose was higher with detemir (1.6 IU/kg/day (95% CI 1.4 to 1.8)) compared with biphasic (1.0 IU/kg/day (95% CI 0.9 to 1.1)) and aspart+detemir (1.1 IU/kg/day (95% CI 1.0 to 1.3)) (p<0.001). Number of participants with severe hypoglycaemia and serious adverse events did not differ. CONCLUSIONS: Carotid IMT change did not differ between 3 insulin regimens despite differences in HbA1c, weight gain and insulin doses. The trial only reached 46% of planned sample size and lack of power may therefore have affected our results. TRIAL REGISTRATION NUMBER: NCT00657943.

Adverse drug reactions associated with the use of liraglutide in patients with type 2 diabetes--focus on pancreatitis and pancreas cancer.

INTRODUCTION: The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide , is a widely used drug for the treatment of type 2 diabetes. Liraglutide is one of several incretin-based agents that have been suggested to be associated with pancreatitis and pancreas cancer. The suspicion accelerated after publication of an autopsy study claiming increased incidences of several pathological changes in pancreata from patients with diabetes treated with incretin-based drugs. AREAS COVERED: The aim of the present review is to give an overview of the pharmacology of liraglutide and provide a review of adverse reactions associated with liraglutide with a focus on the risk of pancreatitis and pancreas cancer. EXPERT OPINION: When comprehensively reviewing the available literature, no clear and significant associations between liraglutide and pancreatitis and/or pancreas cancer seem evident. However, a recently published analysis suggests a trend toward a slightly elevated risk of pancreatitis with GLP-1 receptor agonists (including liraglutide), which may become statistical significant as more data become available. Well-established side effects are of gastrointestinal origin, typical mild-to-moderate and of transient character. The risk of hypoglycemia associated with liraglutide treatment is low.

Out-of-office hours nurse-driven acute telephone counselling service in a large diabetes outpatient clinic: A mixed methods evaluation.

OBJECTIVE: To map the usage of out-of-office hours acute telephone counselling (ATC) provided by diabetes specialist nurses (n=18) for diabetes patients to explore potentials for improvement. METHODS: A mixed methods study involved mapping of ATC-usage during 6 months and a retrospective audit of frequent users. RESULTS: Altogether, 3197 calls were registered that were related to 592 individual patients, corresponding to 10% of the population. Proportionally more users suffered from type 1 diabetes (p<0.001). ATC-users' mean HbA1c was 8.8% (73 mmol/mol) compared to 8.1% (65 mmol/mol) for all patients attending the clinic (p<0.001). Hyperglycaemia was the most frequent reason for calling. The use of ATC likely prevented 15 admissions. More than half of the calls came from general nurses based in the community (n=619) and general nurses and nursing assistants based in care homes (n=1018). The majority (75%) of patients called less than five times. However, 8% called 16 times or more accounting for 52% of all calls. A retrospective audit identified them as physically and/or psychologically fragile patients. CONCLUSION: Hyperglycaemia was the most frequent reason for calling, and insulin dose adjustment the most frequent advice given. PRACTICE IMPLICATIONS: Frequent users identified need additional support.