Real-World Use of Oral Semaglutide in Adults with Type 2 Diabetes: The PIONEER REAL Switzerland Multicentre, Prospective, Observational Study.

INTRODUCTION: Real-world data provide insight into how medications perform in clinical practice. The PIONEER REAL Switzerland study aimed to understand clinical outcomes with oral semaglutide in adults with type 2 diabetes (T2D). METHODS: PIONEER REAL Switzerland was a 34-44-week, multicentre, prospective, non-interventional, single-arm study of adults with T2D naïve to injectable glucose-lowering medication who were initiated on oral semaglutide in routine clinical practice. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline (BL) to end of study (EOS); secondary endpoints included change in body weight (BW) from BL to EOS and the proportion of participants achieving HbA1c < 7.0% and the composite endpoints HbA1c reduction ≥ 1%-points with BW reduction ≥ 3% or ≥ 5% at EOS. Safety was assessed in participants who received ≥ 1 dose of oral semaglutide. RESULTS: Of the 185 participants (female/male, n = 67/118) initiating oral semaglutide, 168 (90.8%) completed the study and 143 (77.3%) remained on treatment with oral semaglutide at EOS. At BL, participants had a mean age of 62 years, diabetes duration of 6.4 years, HbA1c of 7.7%, BW of 95.6 kg and body mass index of 33.2 kg/m2; 56.2% of participants were receiving glucose-lowering medications. Significant reductions were observed for HbA1c (estimated change - 0.91%; 95% confidence interval [CI] - 1.10, - 0.71; p < 0.0001) and BW (estimated change - 4.85%; 95% CI - 5.70, - 4.00; p < 0.0001). In total, 139 adverse events (AEs) were reported in 65 (35.1%) participants; most were mild or moderate. The most frequent AEs were gastrointestinal disorders (27.0%); 31 AEs in 20 (10.8%) participants led to discontinuation of oral semaglutide. Six serious AEs were reported; all were considered unlikely to be related to oral semaglutide. CONCLUSION: People living with T2D treated with oral semaglutide in Switzerland achieved clinically significant reductions in HbA1c and BW, with no new safety signals. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT04537624. A graphical abstract is available for this article.

Presentation of Graves' orbitopathy within European Group On Graves' Orbitopathy (EUGOGO) centres from 2012 to 2019 (PREGO III).

BACKGROUND: Graves' orbitopathy (GO) is subject to epidemiological and care-related changes. Aim of the survey was to identify trends in presentation of GO to the European Group On Graves' Orbitopathy (EUGOGO) tertiary referral centres and initial management over time. METHODS: Prospective observational multicentre study. All new referrals with diagnosis of GO within September-December 2019 were included. Clinical and demographic characteristics, referral timelines and initial therapeutic decisions were recorded. Data were compared with a similar EUGOGO survey performed in 2012. RESULTS: Besides age (mean age: 50.5±13 years vs 47.7±14 years; p 0.007), demographic characteristics of 432 patients studied in 2019 were similar to those in 2012. In 2019, there was a decrease of severe cases (9.8% vs 14.9; p<0.001), but no significant change in proportion of active cases (41.3% vs 36.6%; p 0.217). After first diagnosis of GO, median referral time to an EUGOGO tertiary centre was shorter (2 (0-350) vs 6 (0-552) months; p<0.001) in 2019. At the time of first visit, more patients were already on antithyroid medications (80.2% vs 45.0%; p<0.001) or selenium (22.3% vs 3.0%; p<0.001). In 2019, the initial management plans for GO were similar to 2012, except for lid surgery (2.4% vs 13.9%; p<0.001) and prescription of selenium (28.5% vs 21.0%; p 0.027). CONCLUSION: GO patients are referred to tertiary EUGOGO centres in a less severe stage of the disease than before. We speculate that this might be linked to a broader awareness of the disease and faster and adequate delivered treatment.

Awareness and knowledge of diabetic ketoacidosis in people with type 1 diabetes: a cross-sectional, multicenter survey.

INTRODUCTION: To evaluate awareness and knowledge of diabetic ketoacidosis (DKA), a common and potentially life-threatening complication in people living with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: A survey was developed to assess individuals' current knowledge, management, and unmet needs regarding DKA. The study was conducted in six Swiss and three German endocrine outpatient clinics specialized in the treatment of diabetes. RESULTS: A total of 333 participants completed the questionnaire (45.7% female, mean age of 47 years, average duration of T1D at 22 years). Surprisingly, 32% of individuals were not familiar with the term 'diabetic ketoacidosis'. Participants rated their own knowledge of DKA significantly lower than their physicians (p<0.0001). 46% of participants were unable to name a symptom of DKA, and 45% were unaware of its potential causes. 64% of participants did not test for ketones at all. A significant majority (67%) of individuals expressed the need for more information about DKA. CONCLUSIONS: In patients treated in specialized centers, knowledge of DKA was found to be inadequate, with a lack of understanding regarding symptoms and causes. Healthcare professionals tended to overestimate individuals' knowledge. Future efforts should focus on addressing these knowledge gaps and incorporating protective factors into the treatment of T1D.

Psoriasis immunometabolism: progress on metabolic biomarkers and targeted therapy.

Psoriasis is a common inflammatory disease that affects mainly the skin. However, the moderate to severe forms have been associated with several comorbidities, such as psoriatic arthritis, Crohn's disease, metabolic syndrome and cardiovascular disease. Keratinocytes and T helper cells are the dominant cell types involved in psoriasis development via a complex crosstalk between epithelial cells, peripheral immune cells and immune cells residing in the skin. Immunometabolism has emerged as a potent mechanism elucidating the aetiopathogenesis of psoriasis, offering novel specific targets to diagnose and treat psoriasis early. The present article discusses the metabolic reprogramming of activated T cells, tissue-resident memory T cells and keratinocytes in psoriatic skin, presenting associated metabolic biomarkers and therapeutic targets. In psoriatic phenotype, keratinocytes and activated T cells are glycolysis dependent and are characterized by disruptions in the TCA cycle, the amino acid metabolism and the fatty acid metabolism. Upregulation of the mammalian target of rapamycin (mTOR) results in hyperproliferation and cytokine secretion by immune cells and keratinocytes. Metabolic reprogramming through the inhibition of affected metabolic pathways and the dietary restoration of metabolic imbalances may thus present a potent therapeutic opportunity to achieve long-term management of psoriasis and improved quality of life with minimum adverse effects.

Glucocorticoid withdrawal and glucocorticoid-induced adrenal insufficiency: Study protocol of the randomized controlled «TOASST" (Taper Or Abrupt Steroid STop) multicenter trial.

BACKGROUND: Despite the widespread use of glucocorticoids in inflammatory and autoimmune disorders, there is uncertainty about the safe cessation of long-term systemic treatment, as data from prospective trials are largely missing. Due to potential disease relapse or glucocorticoid-induced hypocortisolism, the drug is often tapered to sub-physiological doses rather than stopped when the underlying disease is clinically stable, increasing the cumulative drug exposure. Conversely, the duration of exposure to glucocorticoids should be minimized to lower the risk of side effects. METHODS: We designed a multicenter, randomized, triple-blinded, placebo-controlled trial to test the clinical noninferiority of abrupt glucocorticoid stop compared to tapering after ≥28 treatment days with ≥420 mg cumulative and ≥7.5 mg mean daily prednisone-equivalent dose. 573 adult patients treated systemically for various disorders will be included after their underlying disease has been stabilized. Prednisone in tapering doses or matching placebo is administered over 4 weeks. A 250 mg ACTH-test, the result of which will be revealed a posteriori, is performed at study inclusion; all patients are instructed on glucocorticoid stress cover dosing. Follow-up is for 6 months. The composite primary outcome measure is time to hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis. Secondary outcomes include the individual components of the primary outcome, cumulative glucocorticoid doses, signs and symptoms of hypocortisolism, and the performance of the ACTH test in predicting the clinical outcome. Cox proportional hazard, linear, and logistic regression models will be used for statistical analysis. CONCLUSION: This trial aims to demonstrate the clinical noninferiority and safety of abrupt treatment cessation after ≥28 days of systemic glucocorticoid therapy in patients with stabilized underlying disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03153527; EUDRA-CT: 2020-005601-48 https://clinicaltrials.gov/ct2/show/NCT03153527?term=NCT03153527&draw=2&rank=1.

Impact of Albumin-to-Creatinine Ratio Point-of-Care Testing on the Diagnosis and Management of Diabetic Kidney Disease.

BACKGROUND: For the diagnosis of diabetic kidney disease (DKD), quantitative albuminuria measurement using the albumin-to-creatinine ratio (ACR) is recommended according to various guidelines. It can be measured either in specialized laboratories or using ACR point-of-care testing (POCT). This observational study aims at evaluating the effect of ACR POCT utilization on the DKD diagnosis and treatment management for glycemic control and blood pressure. METHOD: Data of 717 patients with diabetes (type 1 diabetes: n = 236; type 2 diabetes: n = 463; other diabetes forms: n = 18) were assessed in three centers. The impact of ACR POCT on DKD diagnosis and treatment management for glycemic control and blood pressure was assessed using a case report form. The assessment of ACR POCT utilization purpose and relevance for physicians was documented using a questionnaire. RESULTS: Of all participants (n = 717), 39.1% had a confirmed/suspected DKD diagnosis. Hereof, 8.6% were newly diagnosed with DKD, and 9.9% were suspected with DKD based on the actual ACR POCT values. Within the group of patients with confirmed/suspected DKD (n = 280), treatment modification was performed in 46.1% of participants. A drug initiation with GLP-1 receptor agonists or SGLT2 inhibitors was performed in 11.1% or 8.9% of patients with confirmed/suspected DKD, respectively. Regarding the utilization purposes of ACR POCT, 100% of the physicians (n = 8) indicated using it to examine patients with diabetes with or without hypertension; 75% considered it very important for patients with diabetes. CONCLUSIONS: The implementation of ACR POCT may positively affect DKD diagnosis and subsequently allow better management of patients with diabetes.

Real-world use of once-weekly semaglutide in patients with type 2 diabetes: pooled analysis of data from four SURE studies by baseline characteristic subgroups.

INTRODUCTION: This post hoc pooled analysis of four real-world studies (SURE Canada, Denmark/Sweden, Switzerland and UK) aimed to characterize the use of once-weekly (OW) semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: The Semaglutide Real-world Evidence (SURE) studies had a duration of ~30 weeks. Changes in glycated hemoglobin (HbA1c) and body weight (BW) were analyzed for the overall population and the following baseline subgroups: GLP-1RA-naïve/GLP-1RA switchers; body mass index <25/≥25-<30/≥30-<35/≥35 kg/m2; age <65/≥65 years; HbA1c <7%/≥7-≤8%/>8-≤9%/>9%; T2D duration <5/≥5-<10/≥10 years. Data for patients achieving treatment targets were analyzed in the overall population and the baseline HbA1c ≥7% subgroup. RESULTS: Of 1212 patients, 960 were GLP-1RA-naïve and 252 had switched to semaglutide from another GLP-1RA. In the overall population, HbA1c was reduced from baseline to end of study (EOS) by -1.1% point and BW by -4.7 kg; changes were significant for all subgroups. There were significantly larger reductions of HbA1c and BW in GLP-1RA-naïve versus GLP-1RA switchers and larger reductions in HbA1c for patients with higher versus lower baseline HbA1c. At EOS, 52.6% of patients in the overall population achieved HbA1c <7%. No new safety concerns were identified in any of the completed SURE studies. CONCLUSIONS: In this pooled analysis, patients with T2D initiating OW semaglutide showed significant improvements from baseline to EOS in HbA1c and BW across various baseline subgroups, including patients previously treated with a GLP-1RA other than semaglutide, supporting OW semaglutide use in clinical practice. TRAIL REGISTRATION NUMBERS: NCT03457012; NCT03631186; NCT03648281; NCT03876015.

Excess Body Weight and Abdominal Hernia.

BACKGROUND: Obese patients have an increased incidence of ventral hernias; in over 50% of these cases, patients are symptomatic. At the same time, morbid obesity is a disease of epidemic proportions. The combination of symptomatic hernia and obesity is a challenge for the treating surgeon, because the risk of perioperative complications and recurrence increases with increasing BMI. SUMMARY: This review outlines this problem and discusses interdisciplinary approaches to the management of affected patients. In emergency cases, the hernia is treated according to the surgeon's expertise. In elective cases, an individual decision must be made whether bariatric surgery is indicated before hernia repair or whether both should be performed simultaneously. After bariatric surgery a weight reduction of 25-30% of total body weight in the first year can be achieved and it is often advantageous to perform a bariatric operation prior to hernia repair. Technically, the risk of complications is lower with minimally invasive procedures than with open ones, but laparoscopy is challenging in obese patients, and meshes can only be implanted in intraperitoneal position. This mesh position has to be questioned because of adhesions, recurrence rate, and risk of contamination during re-interventions in patients who are often still relatively young. KEY MESSAGES: Obese patients with hernia need to be approached in an interdisciplinary manner, in some patients a weight loss procedure may be advantageous before hernia repair. Recent data show the benefits of robotic hernia surgery in obese patients, as not only haptic advantages result, but especially the mesh can be implanted in a variety of extraperitoneal positions in the abdominal wall with low morbidity.

Real-world use of once-weekly semaglutide in patients with type 2 diabetes: Results from the SURE Switzerland multicentre, prospective, observational study.

AIMS: SURE Switzerland (NCT03631186) investigated real-world once-weekly (OW) semaglutide use in adults with type 2 diabetes (T2D). METHODS: This multicentre, prospective, observational study enrolled adults with T2D with ≥ 1 documented HbA1c value ≤ 12 weeks before semaglutide initiation. Primary endpoint was change in HbA1c from baseline to end of study (EOS; ~30 weeks). Secondary endpoints included changes in body weight (BW) and waist circumference (WC), and the proportion of patients achieving HbA1c < 8.0%, <7.5% and <7.0% at EOS. Semaglutide dose at EOS was a prespecified exploratory endpoint. RESULTS: Overall, 214 patients initiated semaglutide (baseline HbA1c 7.8% [62 mmol/mol], BW 99.9 kg and WC 117.4 cm); 187 attended the EOS visit. At EOS, 175 (81.8%) were still receiving semaglutide (mean [SD] dose 0.78 [0.29] mg); in those patients, mean HbA1c reduced by -0.8 [95% CI - 1.01;-0.68] %-points (-9 [-11;-7] mmol/mol), BW by -5.0 kg [-5.73;-4.24] and WC by -4.8 cm [-5.75;-3.79] (all p < 0.0001). At EOS, 85.9%, 76.5% and 55.9% patients achieved, respectively, HbA1c < 8.0%, <7.5% and < 7.0%. No new safety signals were identified. CONCLUSIONS: Patients with T2D in Switzerland initiating OW semaglutide experienced clinically relevant glycaemic control and BW improvements in a real-world setting, supporting semaglutide use in routine clinical practice.

Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial.

Importance: The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown. Objective: To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly. Design, Setting, and Participants: Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes. Interventions: A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups. Main Outcomes and Measures: The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]). Results: Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%). Conclusions and Relevance: Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT03548987.

Switch-to-Semaglutide Study (STS-Study): a Retrospective Cohort Study.

INTRODUCTION: Despite expert consensus guidelines, data is scarce on how to switch patients with type 2 diabetes when treatment with glucagon-like peptide 1 (GLP-1) receptor agonists is not effective and whether a switch to semaglutide brings any benefit on glucose and weight control for patients with type 2 diabetes. METHODS: Retrospective cohort analysis of patients with type 2 diabetes who were switched from any GLP-1 agonist in a stable dose to subcutaneously administered semaglutide. Primary endpoint was change of glycated haemoglobin (HbA1c) at 6 months. Secondary endpoints were weight, body mass index (BMI), heart rate, blood pressure and adverse events. RESULTS: In total, 77 patients (median age 65 years) with long-standing type 2 diabetes (median 15 years, median HbA1c 8.4%/68 mmol/l, median BMI 33 kg/m2) were included. HbA1c was significantly lower 6 months after switching to semaglutide (7.3%; 56 mmol/l). Median body weight was significantly lower at 3 months (94 kg) and 6 months (93 kg) compared to baseline (98 kg). An equipotential dose switch of semaglutide was used in 61 patients (79%) and a stepwise initiation approach was used in 16 patients (21%). Both treatment regimens improved glucose control and weight. Side effects occurred in 28 patients (36%). CONCLUSION: Switching to semaglutide from established GLP-1 analogue therapy improved HbA1c and body weight. Both equipotential and stepwise dosing initiation appear to be effective and well tolerated.

Mental Health Among Medical Professionals During the COVID-19 Pandemic in Eight European Countries: Cross-sectional Survey Study.

BACKGROUND: The death toll of COVID-19 topped 170,000 in Europe by the end of May 2020. COVID-19 has caused an immense psychological burden on the population, especially among doctors and nurses who are faced with high infection risks and increased workload. OBJECTIVE: The aim of this study was to compare the mental health of medical professionals with nonmedical professionals in different European countries during the COVID-19 pandemic. We hypothesized that medical professionals, particularly those exposed to COVID-19 at work, would have higher levels of depression, anxiety, and stress. We also aimed to determine their main stressors and most frequently used coping strategies during the crisis. METHODS: A cross-sectional online survey was conducted during peak COVID-19 months in 8 European countries. The questionnaire included demographic data and inquired whether the participants were exposed to COVID-19 at work or not. Mental health was assessed via the Depression Anxiety Stress Scales32 (23.53)-21 (DASS-21). A 12-item checklist on preferred coping strategies and another 23-item questionnaire on major stressors were completed by medical professionals. RESULTS: The sample (N=609) consisted of 189 doctors, 165 nurses, and 255 nonmedical professionals. Participants from France and the United Kingdom reported experiencing severe/extremely severe depression, anxiety, and stress more often compared to those from the other countries. Nonmedical professionals had significantly higher scores for depression and anxiety. Among medical professionals, no significant link was reported between direct contact with patients with COVID-19 at work and anxiety, depression, or stress. "Uncertainty about when the epidemic will be under control" caused the most amount of stress for health care professionals while "taking protective measures" was the most frequently used coping strategy among all participants. CONCLUSIONS: COVID-19 poses a major challenge to the mental health of working professionals as a considerable proportion of our participants showed high values for depression, anxiety, and stress. Even though medical professionals exhibited less mental stress than nonmedical professionals, sufficient help should be offered to all occupational groups with an emphasis on effective coping strategies.

A Clinical Trial for the Identification of Metabolic Biomarkers in Hashimoto's Thyroiditis and in Psoriasis: Study Protocol.

Hashimoto's thyroiditis and psoriasis are inflammatory disorders that significantly impact patients' quality of life, stressing the need for novel biomarkers of early diagnosis. This randomized clinical trial (NCT04693936) aims to identify Hashimoto's thyroiditis' and psoriasis' metabolic biomarkers and to investigate the effect of environmental factors on the disease-related metabolic imprint and quality of life. Patients with Hashimoto's thyroiditis, patients with psoriasis, and healthy individuals aged 18-60 will be recruited, enrolled according to eligibility criteria (medical history, clinical thyroid markers and the PASI score) and randomized to two groups. The intervention group will receive a combination of nutraceuticals for 6 months as part of a Mediterranean diet, and the control group will follow their usual diet. Data will be collected at baseline and the end of the study, including metabolite levels, lifestyle and anthropometric measurements, adherence to the Mediterranean diet (through the Mediterranean Diet Score) and disease-specific quality of life (through the Thyroid Patient Report Outcome for Hashimoto's group, and the Dermatology Life Quality Index for the psoriasis group). This study will investigate metabolic biomarkers and related changes in Hashimoto's thyroiditis and psoriasis and evaluate the association of metabolic changes with dietary factors and quality of life.

snRNA-seq reveals a subpopulation of adipocytes that regulates thermogenesis.

Adipose tissue is usually classified on the basis of its function as white, brown or beige (brite)1. It is an important regulator of systemic metabolism, as shown by the fact that dysfunctional adipose tissue in obesity leads to a variety of secondary metabolic complications2,3. In addition, adipose tissue functions as a signalling hub that regulates systemic metabolism through paracrine and endocrine signals4. Here we use single-nucleus RNA-sequencing (snRNA-seq) analysis in mice and humans to characterize adipocyte heterogeneity. We identify a rare subpopulation of adipocytes in mice that increases in abundance at higher temperatures, and we show that this subpopulation regulates the activity of neighbouring adipocytes through acetate-mediated modulation of their thermogenic capacity. Human adipose tissue contains higher numbers of cells of this subpopulation, which could explain the lower thermogenic activity of human compared to mouse adipose tissue and suggests that targeting this pathway could be used to restore thermogenic activity.

Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study): 52-week results from a randomized controlled trial.

AIM: To investigate the long-term efficacy and safety of dapagliflozin as an adjunct to adjustable insulin in adults with type 1 diabetes (T1D) and inadequate glycaemic control. MATERIALS AND METHODS: Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes (DEPICT-2) was a placebo-controlled, double-blind, multicentre, phase III study of adults with T1D (HbA1c 7.5%-10.5%) randomized (1:1:1) to receive dapagliflozin 5, 10 mg, or placebo. The efficacy and safety of dapagliflozin over 52 weeks were exploratory endpoints in this extension to DEPICT-2. RESULTS: Of 813 participants randomized, 88.2% completed the study. From baseline to 52 weeks, dapagliflozin 5 and 10 mg were associated with reduction in HbA1c (difference [95% CI] vs. placebo: -0.20% [-0.34, -0.06] and -0.25% [-0.38, -0.11], respectively) and adjusted mean percentage change in body weight (difference [95% CI] vs. placebo: -4.42% [-5.19, -3.64] and -4.86% [-5.63, -4.08], respectively). Serious adverse events were reported in the dapagliflozin 5, 10 mg, and placebo groups (32 [11.8%], 19 [7.0%] and 16 [5.9%], respectively). The proportion of hypoglycaemic events was similar across groups; severe hypoglycaemia was uncommon. More participants with events adjudicated as definite diabetic ketoacidosis (DKA) were in the dapagliflozin 5 and 10 mg groups versus placebo (11 [4.1%], 10 [3.7%] and 1 [0.4%], respectively); the majority of events were mild or moderate in severity and all were resolved with treatment. CONCLUSIONS: Dapagliflozin led to long-term reductions in HbA1c and body weight in adults with T1D, but increased DKA risk compared with placebo.

Postprandial Hypoglycemia in Patients after Gastric Bypass Surgery Is Mediated by Glucose-Induced IL-1ß.

Postprandial hypoglycemia is a disabling complication of the treatment of obesity by gastric bypass surgery. So far, no therapy exists, and the underlying mechanisms remain unclear. Here, we hypothesized that glucose-induced IL-1ß leads to an exaggerated insulin response in this condition. Therefore, we conducted a placebo-controlled, randomized, double-blind, crossover study with the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra (clinicaltrials.govNCT03200782; n = 12). Both drugs reduced postprandial insulin release and prevented hypoglycemia (symptomatic events requiring rescue glucose: placebo = 7/12, empagliflozin = 2/12, and anakinra = 2/12, pvallikelihood ratio test (LRT) = 0.013; nadir blood glucose for placebo = 2.4 mmol/L, 95% CI 2.18-2.62, empagliflozin = 2.69 mmol/L, 95% CI 2.31-3.08, and anakinra = 2.99 mmol/L, 95% CI 2.43-3.55, pvalLRT = 0.048). Moreover, analysis of monocytes ex vivo revealed a hyper-reactive inflammatory state that has features of an exaggerated response to a meal. Our study proposes a role for glucose-induced IL-1ß in postprandial hypoglycemia after gastric bypass surgery and suggests that SGLT2-inhibitors and IL-1 antagonism may improve this condition.

Pleiotropic Effect of Lipoprotein-Apheresis on the Soluble Form of Activated Leukocyte Cell Adhesion Molecule (sALCAM) in Familial Hypercholesterolaemia.

INTRODUCTION/BACKGROUND: Atherosclerosis is an inflammatory disorder in which several converging immune responses modulate and induce lipid accumulation in macrophages. Activated leukocyte cell adhesion molecule (ALCAM) has been described as a structural homologue of HDL-receptor and functions as a pattern recognition receptor (PRR), while its soluble form sALCAM is involved in ALCAM-dependent and -independent immune mechanisms. The aim of this study was to investigate the effect of aggressive removal of low density lipoprotein-cholesterol (LDL-C) and lipoprotein(a) (Lp [a]) by lipoprotein-apheresis (LA) on sALCAM and blood viscosity as well as to evaluate its association with lipoproteins and serum markers of inflammation.

BRAF V600E and Retinoic Acid in Radioiodine-Refractory Papillary Thyroid Cancer.

Radioiodine refractoriness in differentiated thyroid cancer remains an unsolved therapeutic problem. Response to retinoids might depend on specific genetic markers. In this retrospective analysis, associations between BRAF V600E and clinical outcomes after redifferentiation with retinoic acid (RA) and radioiodine therapy (RIT) were investigated. Thirteen patients with radioiodine-refractory (RAI-R) papillary thyroid cancer (PTC) were treated with 13-cis-RA followed by iodine-131 treatment at the Department of Endocrinology, Heidelberg University Hospital, Heidelberg, Germany. DNA sequencing was performed in formalin-fixed paraffin-embedded tissue. Clinical outcome parameters were tumor size, thyroglobulin, and radioiodine uptake in correlation to mutational status. Differences of each parameter were compared before and after RA/RIT. Initial response showed no difference in patients with BRAF V600E compared to patients with wild type. However, after a median follow-up of 2 and a half years, 2 out of 3 patients with BRAF V600E showed response compared to 5 out of 9 with wild type under consideration of all 3 parameters. In this small cohort, more RAI-R PTC patients with BRAF V600E receiving redifferentiation therapy showed response. Verification in a larger study population analyzing mutational status in patients with RAI-R PTC might be helpful to identify patients where redifferentiation therapy might lead to an improved outcome.

BATLAS: Deconvoluting Brown Adipose Tissue.

Recruitment and activation of thermogenic adipocytes have received increasing attention as a strategy to improve systemic metabolic control. The analysis of brown and brite adipocytes is complicated by the complexity of adipose tissue biopsies. Here, we provide an in-depth analysis of pure brown, brite, and white adipocyte transcriptomes. By combining mouse and human transcriptome data, we identify a gene signature that can classify brown and white adipocytes in mice and men. Using a machine-learning-based cell deconvolution approach, we develop an algorithm proficient in calculating the brown adipocyte content in complex human and mouse biopsies. Applying this algorithm, we can show in a human weight loss study that brown adipose tissue (BAT) content is associated with energy expenditure and the propensity to lose weight. This online available tool can be used for in-depth characterization of complex adipose tissue samples and may support the development of therapeutic strategies to increase energy expenditure in humans.