The Effect of Insulin Degludec Versus Insulin Glargine U100 on Glucose Metrics Recorded During Continuous Glucose Monitoring in People With Type 1 Diabetes and Recurrent Nocturnal Severe Hypoglycemia.

AIM: Comparing continuous glucose monitoring (CGM)-recorded metrics during treatment with insulin degludec (IDeg) versus insulin glargine U100 (IGlar-100) in people with type 1 diabetes (T1D) and recurrent nocturnal severe hypoglycemia. MATERIALS AND METHODS: This is a multicenter, two-year, randomized, crossover trial, including 149 adults with T1D and minimum one episode of nocturnal severe hypoglycemia within the last two years. Participants were randomized 1:1 to treatment with IDeg or IGlar-100 and given the option of six days of blinded CGM twice during each treatment. CGM traces were reviewed for the percentage of time-within-target glucose range (TIR), time-below-range (TBR), time-above-range (TAR), and coefficient of variation (CV). RESULTS: Seventy-four participants were included in the analysis. Differences between treatments were greatest during the night (23:00-06:59). Treatment with IGlar-100 resulted in 54.0% vs 49.0% with IDeg TIR (70-180 mg/dL) (estimated treatment difference [ETD]: -4.6%, 95% confidence interval [CI]: -9.1, -0.0, P = .049). TBR was lower with IDeg at level 1 (54-69 mg/dL) (ETD: -1.7% [95% CI: -2.9, -0.5], P < .05) and level 2 (<54 mg/dL) (ETD: -1.3% [95% CI: -2.1, -0.5], P = .001). TAR was higher with IDeg compared with IGlar-100 at level 1 (181-250 mg/dL) (ETD: 4.0% [95% CI: 0.8, 7.3], P < .05) and level 2 (> 250 mg/dL) (ETD: 4.0% [95% CI: 0.8, 7.2], P < .05). The mean CV was lower with IDeg than that with IGlar-100 (ETD: -3.4% [95% CI: -5.6, -1.2], P < .05). CONCLUSION: For people with T1D suffering from recurrent nocturnal severe hypoglycemia, treatment with IDeg, compared with IGlar-100, results in a lower TBR and CV during the night at the expense of more TAR.

Effect of insulin degludec versus insulin glargine U100 on nocturnal glycaemia assessed by plasma glucose profiles in people with type 1 diabetes prone to nocturnal severe hypoglycaemia.

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.

Continuous Glucose Monitoring-Recorded Hypoglycemia with Insulin Degludec or Insulin Glargine U100 in People with Type 1 Diabetes Prone to Nocturnal Severe Hypoglycemia.

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 < 0.05) in nocturnal CGM-recorded hypoglycemia (≤3.9 mmol/L), corresponding to an absolute rate reduction (ARR) of 0.85 events per person-week. In nocturnal CGM-recorded hypoglycemia (≤3.0 mmol/L), we found an RRR of 53% (95% CI: 36%-65%; P < 0.001), corresponding to an ARR of 0.75 events per person-week. At the lower detection limit of the CGM (≤2.2 mmol/L), treatment with insulin degludec resulted in a significant RRR of 58% (95% CI: 23%-77%; P = 0.005). The reductions were primarily due to significant RRRs in asymptomatic hypoglycemia. Conclusion: In people with T1D, prone to nocturnal severe hypoglycemia, insulin degludec compared with insulin glargine U100 significantly reduces nocturnal CGM-recorded hypoglycemia. www.clinicaltrials.gov (#NCT02192450).

Contact activated kallikrein generation is reduced six months after gastric bypass.

BACKGROUND: Prothrombotic and inflammatory variables decrease after obesity surgery. The contact activation system may be a common denominator of these changes. OBJECTIVE: To characterize the contact system before and 6 months after Roux-en-Y gastric bypass (RYGB) and to evaluate associations with changes (post-surgery minus pre-surgery) in metabolic variables. METHODS: Women (n = 42) and men (n = 18) with obesity underwent RYGB, and measures of kallikrein generation, factor XII (FXII), prekallikrein, high molecular weight kininogen (HK), and C1 esterase inhibitor (C1-inh) were determined before and 6 months after surgery. Associations were evaluated using correlation and multivariate regression analyses. RESULTS: After RYGB, the endogenous kallikrein potential (EKP), peak kallikrein generation, FXII, and prekallikrein were reduced, and kallikrein generation lag time was prolonged (all p < 0.0005). Before and after RYGB, absolute values of EKP, lag time, and peak kallikrein generation correlated consistently with contact system proteins (range of correlation coefficients (rS): -0.43 to -0.28 and 0.24 to 0.45 (pre-surgery); -0.43 to -0.30 and 0.28 to 0.50 (post-surgery)). RYGB-associated changes in EKP correlated with C1-inh (rS = -0.29, p = 0.025), but also with triglycerides (rS = 0.34, p = 0.007) and cholesterol (rS = 0.28, p = 0.029), and independently associated with changes in C1-inh (ß = -0.40) and triglycerides (ß = 0.39). Changes in C1-inh associated with reductions in body weight (ß = -0.39) and HbA1c (ß = 0.38). CONCLUSION: The contact system was affected 6 months after RYGB. Absolute values of kallikrein generation before and after RYGB correlated with contact system proteins, whereas changes after RYGB associated with changes in C1-inh and metabolic variables.

Effect of bariatric surgery on employment status-a 7 years controlled nationwide registry study.

BACKGROUND: Severe obesity is associated with a reduced ability to work. Bariatric surgery is the most effective method to achieve a sustained weight loss. Previous studies have reported conflicting results regarding the effect of bariatric surgery on employment status. To address this, we investigated the effect of bariatric surgery on employment status in the Danish population. METHODS: In this nationwide study, we identified 5450 subjects who underwent bariatric surgery and 10 900 control subjects matched for age, sex and municipality. From accessible registries, we extracted data regarding employment, absenteeism, sick leave and pension. Using a multistate model, we compared time in occupational states and transitions between these states to determine the effect of bariatric surgery on employment status. FINDINGS: Before surgery, cases had an absolute risk increase (95% CI)(ARI (CI)) and a relative risk (RR (CI)) of being in full-time employment of -0.12 (-0.14 to -0.10) and 0.84 (0.82 to 0.86) and were more often unemployed or in a subsidised job than the background population. Taking into account the employment status before surgery, the bariatric surgery group increased their probability of being in full-time employment 1-3 years after bariatric surgery. However, this positive effect was not present with a longer duration of follow-up. Being male, above 50 years of age, or employed as a craftsman or office worker were associated with a sustained positive effect of being in full-time employment (ARI (CI) and RR (CI) 0.05 (0.04 to 0.05) and 1.05 (1.04 to 1.06), 0.06 (0.06 to 0.07) and 1.08 (1.07 to 1.09) and 0.05 (0.05 to 0.06) and 1.05 (1.05 to 1.06), respectively). INTERPRETATION: Compared with a matched control group, those undergoing bariatric surgery did not improve their employment status in the long term. Certain subgroups had a more sustained positive effect.

Reductions in plasmin inhibitor and fibrinogen predict the improved fibrin clot lysis 6 months after obesity surgery.

Prothrombotic and metabolic variables are decreased after obesity surgery, and fibrin clot lysis is increased. It is unknown how fibrinolytic variables are affected, and whether fibrinolytic and metabolic changes predict the enhanced clot lysis. Study aims were to determine fibrinolytic biomarkers before and 6 months after Roux-en-Y gastric bypass (RYGB) and to identify predictors of the RYGB-induced increase in clot lysis. Women (n = 42) and men (n = 18) with obesity underwent RYGB, and factor XIII (FXIII), thrombin activatable fibrinolysis inhibitor (TAFI), plasminogen and plasmin inhibitor (PI) were measured before and 6 months after surgery. Regression analyses identified determinants of the RYGB-induced increase in clot lysis among changes in fibrinogen and in fibrinolytic and metabolic variables. Results showed that after RYGB, FXIII, TAFI, plasminogen and PI were reduced (P < .0005). Reductions in PI (ß = -0.59) and fibrinogen (ß = -0.35), together with age (ß = -0.22) and male sex (ß = 0.22), predicted the enhanced clot lysis with the model explaining 56% (P < .0005). Predictors of the reduction in PI were reductions in cholesterol (ß = 0.37) and glucose (ß = 0.29), together with male sex (ß = -0.28), whereas reductions in fibrinogen were predicted by lowering of interleukin-6 (IL-6) (ß = 0.32). In conclusion, fibrinolytic variables were reduced 6 months after RYGB. Targeting PI and fibrinogen, by reducing metabolic variables such as glucose, cholesterol and IL-6, has a profibrinolytic effect in obesity.

Attitudes and knowledge regarding referrals for bariatric surgery among Danish secondary healthcare providers: A national survey.

Bariatric surgery induces significant and sustained weight loss and subsequently reduces obesity-related comorbidities. However, only a small percentage of patients with severe obesity undergo bariatric surgery in Denmark. There is limited knowledge about the experiences with and possible reservations to bariatric surgery among secondary healthcare providers. The aim of this cross-sectional study was to investigate referral patterns and knowledge regarding the criteria for bariatric surgery among Danish secondary healthcare providers, treating obesity-related diseases. A questionnaire regarding experiences with and reservations to referring patients for consideration for bariatric surgery, along with thoughts to specific patient cases were sent to several specialists: endocrinologists, obstetricians and gynaecologists, orthopaedic surgeons and otorhinolaryngologists. Most questions required responses on a 5-point Likert scale and frequency distributions were calculated. A total of 345 (44%) specialists responded to the questionnaires. Good knowledge of the criteria for referral to bariatric surgery varied among the specialist from 6% to 68%. One of the main issues was a concern about the medical and surgical postoperative complications, which was a barrier to and influenced referral decisions. Furthermore, specialists were more likely to refer patients to bariatric surgery when patients requested this. Except for endocrinologists, the Danish secondary healthcare specialists interviewed have limited knowledge about bariatric surgery, which results in a reluctance in referring patients. Our results indicate that there is a need to improve knowledge among specialists, regarding the indications, criteria and outcomes for bariatric surgery to establish a more pro-active, specialist led approach to referrals.

Effects of Obesity Surgery on Blood Coagulation and Fibrinolysis: A Literature Review.

OBJECTIVE: Obesity is characterized by a disturbed hemostatic balance with increased coagulation and impaired fibrinolysis. This increases the risk of thrombosis, and the risk is lowered after obesity surgery. Over the past 25 years, several studies have contributed to understand the mechanisms behind the antithrombotic effect of obesity surgery, and this literature review summarizes the results of these studies. METHODS: A detailed literature search on the effects of obesity surgery on the hemostatic balance was conducted. RESULTS: The 25 relevant studies reviewed demonstrated that obesity surgery has favorable effects on many biomarkers of coagulation and fibrinolysis. The evidence is substantial for fibrinogen and plasminogen activator inhibitor type 1 with average reductions from 1 to 24 months after obesity surgery of 17 and 48%, respectively. For most other biomarkers, the evidence is moderate or weak with average effect sizes varying from 2% for fiber mass length ratio to 70% for prothrombin fragment 1 + 2 and with a large variation between studies. Many studies are small and of short duration, and the surgical techniques differ. Also, studies are confounded by changes in medication, comorbidity, diet, and exercise. It is unknown whether the hemostatic changes are mediated by weight loss alone or by the accompanying metabolic improvements. CONCLUSION: Despite issues of confounding, this review suggests that obesity surgery shifts the hemostatic balance in the antithrombotic direction, thereby reducing the thrombotic potential of people with obesity, but more studies are needed for most of the biomarkers.

Physical training following gastric bypass: effects on physical activity and quality of life-a randomized controlled trial.

BACKGROUND: Obesity is associated with physical inactivity and impaired health-related quality of life (HRQoL). We aim to test the hypothesis that Roux-en-Y gastric bypass (RYGB) followed by supervised physical training improves physical activity (PA) levels and HRQoL. METHODS: Sixty patients, qualified for RYGB, were at 6 months post-surgery randomized to 26 weeks of a supervised physical training intervention (INT) or to a control (CON) group. PA was assessed by accelerometry and using the questionnaire RPAQ. HRQoL was measured by the SF-36 questionnaire. All assessments were performed pre-surgery and 6, 12, and 24 months post-surgery. RESULTS: RYGB did not improve objectively or self-reported PA, but improved all domains of SF-36 (all p < 0.01). Objectively measured light PA, moderate to vigorous PA, and step counts tended to increase in INT compared to CON 12 months after RYGB (0.05 < p < 0.09), but the effects failed to persist. The SF-36 domain "general health" increased in INT compared to CON 24 months after RYGB (p = 0.041). CONCLUSION: RYGB improves HRQoL, but does not increase PA. Supervised physical training intervention improves general health 24 months after RYGB and tends to improve certain domains of PA right after the intervention period, but fails to increase the patients' overall PA level over time. Clinical Trial Registration Registered at ClinicalTrials.gov-no. NCT01690728.

Effects of gastric bypass followed by a randomized study of physical training on markers of coagulation activation, fibrin clot properties, and fibrinolysis.

BACKGROUND: The risk of cardiovascular disease is reduced by bariatric surgery, but it is unknown if exercise after bariatric surgery reduces this risk even further. OBJECTIVE: To investigate if Roux-en-Y-gastric bypass (RYGB) and supervised physical training after RYGB improve cardiovascular disease risk markers within coagulation activation, fibrin clot properties, and fibrinolysis. SETTING: Bariatric center, Hospital of Southwest Jutland, Denmark. METHODS: Sixty obese patients underwent RYGB and 6 months after RYGB were randomized to 26 weeks of physical training or a control group. Biomarkers within coagulation activation, fibrin clot properties, and fibrinolysis were measured presurgery, and 6, 12, and 24 months postsurgery. RESULTS: Six months after RYGB, the endogenous thrombin potential decreased from 1744 (1603-2003) to 1416 (1276-1582) nM × min (P<.001). Alterations in fibrin clot properties resulted in an increased clot lysis from 23.8% (16.1%-38.9%) to 40.3% (28.5%-59.35; P<.0001). Furthermore, fibrinogen was reduced from 12.6 (11.1-14.7) to 11.5 (9.90-13.3) µM (P<.001), and plasminogen activator inhibitor antigen was reduced from 40.5 (28.4-49.4) to 24.4 (15.4-32.7) ng/mL (P<.0001). Physical training after RYGB increased fibrinolytic activity from 58.0 (36.0-75.5) to 88.0 (66.0-132.0) IU/mL compared with 52.5 (30.0-80.0) to 64.0 (49.0-100.0) IU/mL in controls (P<.01) and reduced plasminogen activator inhibitor antigen from 23.5 (16.7-35.4) to 18.1 (14.3-25.4) ng/mL compared with 24.4 (13.9-28.7) to 24.2 (14.1-29.6) ng/mL in controls (P<.05). No effects of physical training were observed on markers of coagulation activation and fibrin clot properties. CONCLUSION: We observed favorable long-term reductions in markers of thrombin generation, improved fibrin clot properties, and increases in fibrinolysis after RYGB. Supervised physical training after RYGB further increased fibrinolysis.

Effects of gastric bypass surgery followed by supervised physical training on inflammation and endothelial function: A randomized controlled trial.

BACKGROUND AND AIMS: Obesity and physical inactivity are both associated with low-grade inflammation and endothelial dysfunction. Bariatric surgery improves markers of inflammation and endothelial function, but it is unknown if physical training after bariatric surgery can improve these markers even further. Therefore, we aimed to investigate the effects of Roux-en-Y gastric bypass (RYGB) followed by physical training on markers of low-grade inflammation and endothelial function. METHODS: Sixty patients approved for RYGB underwent examinations pre-surgery, 6, 12, and 24 months post-surgery. Six months post-surgery, they were randomized 1:1 to an intervention group or a control group. The interventions consisted of two weekly sessions of supervised moderate intensity physical training for a period of 26 weeks. Fasting blood samples were analyzed for concentrations of interleukin 6 (IL-6), C-reactive protein (CRP), intercellular adhesion molecule 1 (ICAM-1), tissue-type plasminogen activator antigen (t-PA:Ag) and von Willebrand factor (vWF). RESULTS: RYGB markedly improved markers of inflammation (IL-6, CRP) (p < 0.001) and endothelial function (ICAM-1, t-PA:Ag, vWF) (p < 0.05), and the improvements were sustained 24 months post-surgery (p < 0.01), except for the effects on vWF. We found no correlations between the changes in weight or BMI and the changes in markers of inflammation and endothelial function, except that the change in vWF was found to be inversely correlated with the changes in weight and BMI. We observed no effects of supervised physical training on markers on inflammation or endothelial function (p>0.1 for all). CONCLUSIONS: RYGB causes substantial and sustained favorable effects on markers of inflammation and endothelial function. Supervised physical training after RYGB did not cause additional improvements.

Supervised Physical Training Improves Weight Loss After Roux-en-Y Gastric Bypass Surgery: A Randomized Controlled Trial.

OBJECTIVE: Bariatric surgery results in significant weight loss and reduces cardiovascular morbidity. However, a large variation in postsurgery weight loss is seen. Physical activity promotes weight loss in nonsurgically treated subjects with obesity. The aim of this study was to investigate the effects of 6 months of supervised physical training following Roux-en-Y gastric bypass surgery (RYGB) on body weight and cardiovascular risk markers. METHODS: Sixty participants eligible for RYGB were included. Six months post surgery, the participants were randomly assigned to either twice-weekly supervised physical training sessions in a fitness center (INT) or a control group (CON) for 26 weeks. Before surgery and 6, 12, and 24 months after surgery, the participants underwent an examination program that included anthropometric measurements, blood pressure, heart rate, blood samples, and an abdominal computed tomography scan. RESULTS: RYGB significantly reduced body weight and improved cardiovascular risk markers (all P < 0.01). The supervised physical training intervention resulted in a 4.2-kg (CI: -0.2 to -8.3 kg) lower body weight in INT compared with CON at the study end (P = 0.042). The high-density lipoprotein concentration was significantly higher in INT than in CON at the termination of the intervention, but this was not maintained at the 24-months examination. CONCLUSIONS: Physical training following RYGB improves weight loss and cardiovascular health.

Primary care physician decision making regarding referral for bariatric surgery: a national survey.

BACKGROUND: Bariatric surgery is the most effective treatment for severe obesity. It results in significant and sustained weight loss and reduces obesity-related co-morbidities. Despite an increasing prevalence of severe obesity, the number of bariatric operations performed in Denmark has decreased during the past years. This is only partly explained by changes in the national guidelines for bariatric surgery. The purpose of the cross-sectional study is to investigate referral patterns and possible reservations regarding bariatric surgery among Danish primary care physicians (PCPs). SETTING: Primary care physicians in Denmark METHODS: A total of 300 Danish PCPs were invited to participate in a questionnaire survey regarding experiences with bariatric surgery, reservations about bariatric surgery, attitudes to specific patient cases, and the future treatment of severe obesity. Most questions required a response on a 5-point Likert scale (strongly disagree, disagree, neither agree nor disagree, agree, and strongly agree) and frequency distributions were calculated. RESULTS: 133 completed questionnaires (44%) were returned. Most physicians found that they had good knowledge about the national referral criteria for bariatric surgery. With respect to the specific patient cases, a remarkably smaller part of physicians would refer patients on their own initiative, compared with the patient's initiative. Fear of postoperative surgical complications and medical complications both influenced markedly the decision to refer patients for surgery. Only 9% of the respondents indicated that bariatric surgery should be the primary treatment option for severe obesity in the future. CONCLUSION: Danish PCPs express severe concerns about surgical and medical complications following bariatric surgery. This might, in part, result in a low rate of referral to bariatric surgery.