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Glucagon-like peptide-1 (GLP-1) receptor agonists mimic the action of the endogenous GLP-1 incretin hormone, improving glycaemic control in type 2 diabetes mellitus (T2DM) by increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner. However, as cardiovascular (CV) morbidity and mortality is common in patients with T2DM, several trials with the use of GLP-1 receptor agonists (RAs) have been performed focusing on endpoints related to cardiovascular disease rather than metabolic control of T2DM. Following the positive cardiovascular effects of liraglutide, dulaglutide and semaglutide observed in these trials, major changes in T2DM management guidelines have occurred. This document from a Eastern and Southern European Diabetes Expert Group discusses the results of GLP-1 RA CV outcomes trials, their impact on recent clinical guidelines for the management of T2DM, and some selected combination regimens utilising GLP-1 RAs. We also propose an algorithm for guiding GLP-1 RA-based treatment according to patients' characteristics, which can be easily applied in every day clinical practice.

Diabetes mellitus je významným rizikovým faktorem rozvoje srdecniho selhani a přitomnost diabetu zaroveň zhorsuje prognozu nemocných se srdecnim selhanim. Jednou z významných novinek v lecbě srdecniho selhani jsou glifloziny, ktere blokadou reabsorpce glukozy v proximalnim tubulu diky inhibici sodiko-glukozoveho kotransporteru 2 vedou ke sniženi glykemie navozenim glykosurie. Glifloziny byly a stale jsou primarně využivany jako ucinna antidiabetika, ktera kromě zlepseni kompenzace diabetu snižuji tělesnou hmotnost a krevni tlak bez zvýseni rizika hypoglykemie. Studie z poslednich let prokazaly, že glifloziny u diabetiků významně snižuji riziko kardiovaskularnich komplikaci a hospitalizace pro srdecni selhani. Nedavno ukoncene studie s dapagliflozinem a empagliflozinem navic ukazaly významne sniženi kombinace umrti z kardiovaskularnich přicin a hospitalizace pro srdecni selhani u pacientů se srdecnim selhanim s redukovanou ejekcni frakci, a to jak u diabetiků, tak i nediabetiků. Cilem toho clanku je formou expertniho konsenzu shrnout prakticke aspekty spoluprace kardiologa a diabetologa v peci o pacienty s chronickým srdecnim selhanim s redukovanou ejekcni frakci v kontextu soucasných doporuceni a dalsich lecebných možnosti. © 2021, CKS.

Introduction Recent development of novel antidiabetic drugs with proven cardiovascular (CV) and renal benefit and positive effect on body weight enable to take a more complex approach toward the management of type 2 diabetes mellitus (T2DM). Fixed-ratio combinations of insulin-GLP-1 receptor agonist (FRC) utilize complementary mechanisms of action of their individual components and address multiple pathologies linked with T2DM at the same time. Areas covered There are currently three FRCs on the market: iGlarLixi (glargine and lixisenatide in 2 different formulations) and IDegLira (degludec and liraglutide). We provide an up-to-date review on the rationale for the use of FRCs and their current position in the management of T2DM. We discuss the available evidence from randomized controlled trials, post hoc analyses, indirect comparative studies and real-world data on their effect on glycemic control, risk of hypoglycemia, body weight, CV safety, and their safety profile. Expert opinion FRCs represent an efficacious option for treatment intensification from basal insulin or even the first insulin-based therapy in T2DM. Their excellent glucose-lowering efficacy is complemented with lower risk of hypoglycemia in comparison to basal insulin, neutral effect on body weight and the lower risk of gastrointestinal adverse effects in comparison to GLP-1 receptor agonists.

(1) Background: C1q TNF-related protein 3 (CTRP3) is an adipokine with anti-inflammatory and cardioprotective properties. In our study, we explored changes in serum CTRP3 and its gene expression in epicardial (EAT) and subcutaneous (SAT) adipose tissue in patients with and without coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) undergoing elective cardiac surgery. (2) Methods: SAT, EAT, and blood samples were collected at the start and end of surgery from 34 patients: (i) 11 without CAD or T2DM, (ii) 14 with CAD and without T2DM, and (iii) 9 with both CAD and T2DM. mRNA levels ofCTRP3were assessed by quantitative reverse transcription PCR. Circulating levels of CTRP3 and other factors were measured using ELISA and Luminex Multiplex commercial kits. (3) Results: Baseline plasma levels of TNF-α and IL6 did not differ among the groups and increased at the end of surgery. Baseline circulating levels of CTRP3 did not differ among the groups and decreased after surgery. In contrast, baselineCTRP3mRNA levels in EAT were significantly decreased in CAD/T2DM group, while no differences were found forTNF-αandIL6gene expression. (4) Conclusions: Our data suggest that decreased EAT mRNA levels ofCTRP3could contribute to higher risk of atherosclerosis in patients with CAD and T2DM.

(1) Background: C1q TNF-related protein 3 (CTRP3) is an adipokine with anti-inflammatory and cardioprotective properties. In our study, we explored changes in serum CTRP3 and its gene expression in epicardial (EAT) and subcutaneous (SAT) adipose tissue in patients with and without coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) undergoing elective cardiac surgery. (2) Methods: SAT, EAT, and blood samples were collected at the start and end of surgery from 34 patients: (i) 11 without CAD or T2DM, (ii) 14 with CAD and without T2DM, and (iii) 9 with both CAD and T2DM. mRNA levels of

Introduction Obesity and atrial fibrillation (AF) pose a significant burden on healthcare systems worldwide. Reduction of body weight has been documented to reduce the risk of AF. Little is known about the effect of different weight-reducing interventions including bariatric surgery in obese individuals on the risk of arrhythmia recurrence following catheter ablation (CA) for AF, and about the pathophysiological mechanisms linking these two conditions. Methods The Effect of complex weigHt-reducing interventiOns on rhythm control in oBese subjects wITh Atrial Fibrillation (HOBIT-AF) is a single-blinded, parallel-group randomised controlled trial with 18-month follow-up to assess the effect of complex weight-reducing interventions supported by the use of smart technologies and bariatric surgery on the arrhythmia burden in obese individuals following CA for AF. One hundred and sixty individuals (age 18–70 years, body mass index ≥ 30 kg/m2) will be randomised in a 1:1 fashion to undergo a structured weight reduction programme and sleeve gastrectomy (when indicated and preferred by the patient) aiming to achieve greater than 10% weight reduction from baseline (intervention group) or standard post-ablation medical care (control group). Two-week continuous ECG monitoring will be used 3 and 18 months after CA to assess the arrhythmia burden. Other investigations will include transthoracic echocardiography with quantification of epicardial adipose tissue, and markers of low-grade inflammation and circulating adipokines. Planned Outcomes The main objective is to assess the effect of complex weight-reducing interventions on the arrhythmia burden and quality of life. Subgroup analyses to identify patient subgroups preferentially benefiting from weight loss related to a decrease in arrhythmia burden will be performed. Exploratory objectives will include investigation of potential mechanisms linking weight reduction with amelioration of arrhythmia burden such as changes in markers of low-grade inflammation, circulating adipokines, cytokines, monocytes or reduction of epicardial adipose tissue volume. Trial Registration NCT04560387

Context Gestational diabetes mellitus (GDM) is accompanied by subclinical inflammation; however, little is known about local inflammation in adipose tissue and placenta. Objective To analyze systemic and local subclinical inflammation and adipose tissue lymphocyte content and phenotype in pregnant women with and without GDM. Design Observational study. Settings Academic hospital. Patients Twenty-one pregnant women with GDM (GDM group), 16 pregnant women without GDM (non-GDM group) and 15 nonpregnant control women (N group). Interventions Serum samples taken at 28 to 32 (visit 1 [V1]) and 36 to 38 (V2) gestational weeks and 6 to 12 months after delivery (V3) in the GDM and non-GDM group and before elective gynecological surgery in the N group. Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained during cesarean delivery or surgery. Main Outcome Measures Serum levels and adipose tissue expression of proinflammatory cytokines, adipose tissue lymphocyte content and phenotype (for a subset of GDM and non-GDM subjects). Results Accented proinflammatory state in GDM was documented by increased circulating tumor necrosis factor-α (TNF-α) levels. In both groups of pregnant females total lymphocytes were higher in VAT compared to SAT. In GDM subjects B cells and NKT cells were higher in SAT compared to VAT and T helper cells were increased relative to SAT of non-GDM group, while no intercompartmental adipose tissue differences were seen in non-GDM women. Conclusions Pregnant females had higher total lymphocyte count in VAT relative to SAT regardless of GDM. In addition to increased systemic subclinical inflammation, GDM was associated with significant differences in lymphocyte composition between subcutaneous and visceral adipose tissue depots.

Objective Patients with type 2 diabetes (T2DM) generally experience a higher incidence of cancer. However, the association between T2DM and thyroid cancer is inconclusive. Methods Case-control prospective study, where 722 patients were screened for T2DM and prediabetes (PDM) and underwent thyroid ultrasound and biochemical tests. The patients were assigned to groups of PDM (n = 55), T2DM (n = 79) or a non-diabetes group (NDM) (n = 588). Fine-needle aspiration biopsy was carried out in 263 patients. Histological examinations were done for 109 patients after surgery, with findings of 52 benign (BS) and 57 malignant tumors (MS). Results Thirty-three percent of patients with T2DM and especially PDM were newly diagnosed by our screening: 6.5% with T2DM and 72% with PDM, respectively. The percentage of thyroid cancers did not significantly differ between the groups (χ2 test = 0.461; P = 0.794). Relevant positive thyroid predictors for T2DM (t-statistic = 25.87; P P P P P P P Conclusion In general, we did not observe an increased risk for thyroid cancer in the diabetic and prediabetic groups in comparison to controls, in spite of well-established increased risk for other malignancies. Structural and benign changes such as larger and multinodular thyroid glands, in comparison to autoimmune thyroid disease, are present more often in diabetics.

Chronic inflammation of adipose tissue is associated with the pathogenesis of cardiovascular diseases. Mast cells represent an important component of the innate defense system of the organism. In our work, we quantified mast cell number in epicardial adipose tissue (EAT), subcutaneous adipose tissue (SAT), and right atrial myocardium (RA) in patients undergoing open heart surgery (n=57). Bioptic samples of EAT (n=44), SAT (n=42) and RA (n=17) were fixed by 4 % paraformaldehyde and embedded into paraffin. An anti-mast cell tryptase antibody was used for immunohistochemical detection and quantification of mast cells. We also demonstrated immunohistochemically the expression of CD117 and chymase markers. In EAT of patients with coronary artery disease (CAD), higher incidence of mast cells has been found compared to patients without CAD (3.7±2.6 vs. 2.1±1.2 cells/mm(2)). In SAT and RA, there was no difference in the number of mast cells in CAD and non-CAD patients. Mast cells in SAT, EAT and RA expressed CD117 and chymase. An increased incidence of mast cells in EAT of CAD patients may indicate the specific role of these inflammatory cells in relation to EAT and coronary arteries affected by atherosclerosis.

Aims Chronic kidney disease (CKD) challenges diabetes management and is associated with increased cardiovascular morbidity and mortality. We examined whether clinical outcomes with insulin glargine 300 U/mL (Gla‐300) and insulin degludec 100 U/mL (IDeg‐100) are affected by renal function in a prespecified subgroup analysis from the BRIGHT trial. Materials and methods BRIGHT (NCT02738151) was a multicentre, open‐label, randomized, active‐controlled, two‐arm, parallel‐group, 24‐week study in insulin‐naïve uncontrolled type 2 diabetes (T2D). Participants were randomized 1:1 to evening Gla‐300 (n = 466) or IDeg‐100 (n = 463) and stratified based on baseline estimated glomerular filtration rate (eGFR) for this analysis. Results Heterogeneity of treatment effect across renal function subgroups was observed (P = .02), reflecting a greater mean glycated haemoglobin (HbA1c) reduction from baseline to week 24 with Gla‐300 versus IDeg‐100 in the eGFR

Uncertainty exists re risk:benefit of proximal intestinal exclusion with EB, a novel endoscopic duodenal jejunal liner device for obesity, both with and without diabetes. In view of this, during 2017, an independent, secure, on line registry was established under the auspices of the Association of British Clinical Diabetologists, for the collection of safety and efficacy data worldwide. As of December 2021, data had been entered on 10patients {age 52.1 ± 10.3 year, 53% male, 87% diabetes, BMI 41.1 ± 8.9 kg/m2} and showed many benefits (Table 1) . There were 43 (4.2%) SAEs and 139 (13.9%) less serious AEs (Table 2) . All SAE patients made a full recovery and most derived significant benefit. The benefits of EB therapy are likely to reduce the complications of diabetes. This international data from the EB registry suggests that the likely benefits of EB, far outweigh the risks Disclosure R.E.J. Ryder: None. J.P. Teare: None. A. Ruban: None. M. Haluzik: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Abbott Diabetes, AstraZeneca, Lilly Diabetes, Novartis AG. L. Munro: None. H. Frydenberg: None. J.J. McMaster: None. S. Fishman: None. R.V. Cohen: Advisory Panel; GI Dynamics. Research Support; Johnson & Johnson, Medtronic. C.M. Aboud: None. G.J. Holtmann: Research Support; AbbVie Inc., Allergan, Arena Pharmaceuticals, Inc., Bayer, Bristol Myers, Datapharm Australia Pty Ltd Commonwealth Laboratories, Pty Limited, Eli Lilly Australia Pty Limited, F.Hoffmann-La Roche Limited, Falk Foundation, Falk GmbH and Co Kg, GI Therapies Pty Ltd, Gilead Sciences Pty Limited, MedImmune Ltd Celgene Pty Limited, Mylan, Nestle Pty Ltd, Prometheus Laboratories, Quintiles Pty Limited, Servatus, Takeda Development Center Asia, Pty Ltd, Vital Food Processors Ltd. C. de Jonge: None. J. Greve: Advisory Panel; GI Dynamics. Other Relationship; Bariatric Solutions International, Ethicon, Inc. J.C. Mason: None. H. Sourij: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk. Research Support; Boehringer Ingelheim International GmbH, Sanofi. Speaker's Bureau; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk. R. Drummond: Research Support; Fractyl Health, Inc. Speaker's Bureau; AstraZeneca, Bristol-Myers Squibb Company. B. McGowan: Advisory Panel; Johnson & Johnson, Lilly, Novo Nordisk. Research Support; Novo Nordisk. Speaker's Bureau; AstraZeneca, Novo Nordisk. Stock/Shareholder; Reset Health. S.A. Amiel: Advisory Panel; Medtronic, Novo Nordisk. Other Relationship; Sanofi. M. Yadagiri: None. P. Sen Gupta: None. K. Laubner: None. J. Seufert: Advisory Panel; Abbott, Sanofi-Aventis Deutschland GmbH. Research Support; Boehringer Ingelheim International GmbH. Speaker's Bureau; Abbott Diabetes, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. Funding Association of British Clinical Diabetologists

The exact mechanisms behind favorable metabolic and cardioprotective effects of SGLT-2 inhibitors (SGLT-2i) are still not fully understood. We performed a complex metabolomic analysis of subcutaneous (SAT) and epicardial (EAT) adipose tissue of heart failure subjects treated with SGLT-2i in order to assess their impact on different fat depots and identify potential cardioprotective factors. Nine subjects with severe heart failure with reduced ejection fraction (NYHA class III-IV) treated with SGLT-2i and 8 age-, BMI- and left ventricular ejection fraction-matched control subjects scheduled for heart transplantation or mechanical support implantation were included into the study. Eight SGLT-2i subjects and 5 control subjects had type 2 diabetes mellitus. A complex metabolomic analysis of SAT and EAT obtained during surgery was performed using liquid chromatography and mass spectrometry. SAT of SGLT-2i subjects showed marked increase in ketone bodies and a corresponding decrease of ketogenic triacylglycerols with medium-chain fatty acids suggesting enhanced ketogenesis typical for SGLT-2i use. In contrast, no such change was seen in EAT which, conversely, contained increased amount of long-chain triacylglycerols indicating significant differences in response to SGLT-2i treatment between these depots and a tendency to preserve EAT lipid content. Compared with control group, both SAT and EAT of SGLT-2i subjects consistently exerted surprisingly high levels of sphingolipids, especially sphingomyelins and ceramides, and ether-linked lipid species. In conclusion, SGLT-2i treatment leads to different metabolic responses in SAT and EAT with SAT showing mainly accented ketogenesis, while the preservation of EAT suggests other functions including potential cardioprotection. The exact role of increased sphingolipids and ether-linked lipids in both adipose tissue depots remains to be elucidated. Disclosure B.Kasperova: None. I.Pleyerova: None. K.Rosolová: None. P.Svoboda: None. J.Trnovska: None. P.Novodvorsky: Advisory Panel; Novo Nordisk, Sanofi, Other Relationship; Eli Lilly and Company, Sanofi, Research Support; Dexcom, Inc., Speaker's Bureau; Eli Lilly and Company, KRKA, Mundipharma, Novo Nordisk, Sanofi. P.Ivak: Consultant; Abbott, CARMAT SA. V.Melenovsky: Consultant; Bayer AG, Merck Sharp & Dohme Corp., Novo Nordisk, Research Support; Regeneron Pharmaceuticals Inc. I.Netuka: Board Member; LeviticusCardio Ltd., Consultant; Abbott, CARMAT SA. M.Haluzik: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Lilly Diabetes, Novartis AG. M.Mraz: None. O.Kuda: None. T.Cajka: None. D.Hlavácek: None. J.Mahrík: None. L.Tomanová: None. I.Lankova: n/a. S.Stemberkova hubackova: None. Funding Ministry of Health, Czech Republic - conceptual development of research organization („Institute for Clinical and Experimental Medicine – IKEM, IN 00023001“) NV19-02-00118

Pre-Breakfast iGlarLixi efficacy and safety were demonstrated in several randomized controlled trials. Whether time of administration could impact effectiveness in real life clinical practice is unknown. In the European REALI pooled database, we analyzed patient-level data of 1303 people with type 2 diabetes (T2D) treated with iGlarLixi for 24 weeks. Of these, 33% had the injection pre-Breakfast, 20% pre-Lunch, 31% pre-Dinner, while 16% switched time of injection. Overall, baseline characteristics were similar among groups with mean±SD age of 61±9.0 years, BMI 32.2±5.5 kg/m2, and median diabetes duration of 9 years. People with T2D previously used 1 oral glucose-lowering agent (57%) or ≥2 (43%) . A total of 590 people (45%) were insulin pretreated for a median duration of 2.5 years. Mean±SD HbA1c improved from 9.1±1.4% at Baseline to 7.7±1.2% at Week 24, with a least square mean decrease of 1.4% [95% CI: -1.50;-1.36], and most notable reduction in the pre-Breakfast group as shown in Figure 1. Mean±SD fasting plasma glucose decreased by 50.0±54.2 mg/dL and body weight by 1.8±6.6 kg at Week 24 with no difference between groups. Hypoglycemia reports were low in all groups.This analysis confirms the effectiveness of iGlarLixi at all administration times; pre-Breakfast may be preferable when there is a choice. Disclosure M.Haluzik: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Lilly Diabetes, Novartis AG. J.Seufert: Advisory Panel; Abbott, Sanofi-Aventis Deutschland GmbH, Research Support; Boehringer Ingelheim International GmbH, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. C.Guja: Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Servier Laboratories. M.Bonnemaire: Employee; Sanofi. G.Bigot: None. M.Tournay: None. J.T.Kis: Speaker's Bureau; 77 Elektronika Kft., AstraZeneca, Boehringer Ingelheim International GmbH, EGIS Pharmaceuticals, Lilly Diabetes, Novo Nordisk, Sanofi. N.Freemantle: Consultant; Novo Nordisk, Research Support; Aimmune, ALK-Abelló A/S, Allergan, AstraZeneca, Ipsen Biopharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Sanofi, Vertex Pharmaceuticals Incorporated, Speaker's Bureau; Abbott. Funding Sanofi

Adiponectin, adipocyte fatty acid-binding protein (A-FABP), and fibroblast growth factor-19 (FGF-19) belong to proteins involved in glucose metabolism regulation. The aims of the study were to compare the plasma levels of these proteins in women with early diagnosed gestational diabetes mellitus (GDM) to those in healthy controls and to investigate their changes during pregnancy after early intervention.The study was undertaken as a case-control study. Early GDM diagnosis was based on repeated fasting plasma glucose ≥5.1 andlt;7.0 mmol/L during the first trimester of pregnancy and exclusion of overt diabetes. Age-matched controls comprised healthy pregnant and non-pregnant women. In addition to adipokines, clinical parameters and measures of glucose control were assessed.Women with GDM (Women with GDM showed altered adipokine production even in the first trimester of pregnancy. Early therapeutic intervention not only improved glucose control but also normalized impaired adipokine production.

Introduction: Despite the ever-improving medical care, pregnancies of women with type 1 diabetes mellitus (T1DM) are at increased risk of complications for both mother and child. Optimal compensation of diabetes before and during pregnancy is an essential protective factor reducing the risk of congenital malformations, pregnancy loss, and other complications. The pregnancy of women with T1DM should be planned, ideally at a time of optimal diabetes compensation. Target glycated hemoglobin (HbA1c) values until the range of 42–48 mmol/mol should be achieved at least three months before pregnancy. Our work aimed to evaluate the perinatal results of pregnancies in women with T1DM and the eff ect of preconception counseling and adequate T1DM compensation before pregnancy on perinatal outcomes. Methods and results: Retrospective analysis of pregnancy and perinatal outcomes of women with T1DM were followed up at the Department of Gynecology and Obstetrics, General University Hospital in Prague and First Faculty of Medicine, Charles University between 2008 to 2018. A total of 221 women with T1DM were included in the analysis. Adequate (HbA1c ≤ 48 mmol/mol at least 3 months before conception) and inadequate diabetes compensation at the beginning of the pregnancy had 59 (26.7%) and 162 (72.3%) women, respectively. Pregnancies of women with adequate diabetes compensation were more often planned (55.9 vs. 24.7%; P 95th percentile; 22.0 vs. 35.8%; P = 0.027). Conclusion: The pregnancy of women with T1DM is burdened by a number of perinatal and neonatal complications. In the study group, most women with T1DM became pregnant unintentionally at a time of inadequate diabetes compensation. Women who achieved adequate diabetes compensation before pregnancy had a lower incidence of perinatal complications. Therefore, it is advised that women with T1DM should plan their pregnancy, attend preconception and antenatal care, and give birth in perinatal centers, which provide coordinated care from diabetologists, gynecologists, obstetricians, and neonatologists. Key words: preconceptual counseling – type 1 diabetes mellitus – perinatal outcomes

Recent studies suggest that treatment with SGLT-2 inhibitors can reduce hepatic lipid storage and ameliorate non-alcoholic fatty liver disease (NAFLD) development beyond their glycemic benefits. However, the exact mechanism involved is still unclear. We investigated the hepatic metabolic effect of empagliflozin (10 mg/kg/day for eight weeks) on the development of NAFLD and its complications using HHTg rats as a non-obese prediabetic rat model. Empagliflozin treatment reduced neutral triacylglycerols and lipotoxic diacylglycerols in the liver and was accompanied by significant changes in relative mRNA expression of lipogenic enzymes (Scd-1, Fas) and transcription factors (Srebp1, Pparγ). In addition, alterations in the gene expression of cytochrome P450 proteins, particularly Cyp2e1 and Cyp4a, together with increased Nrf2, contributed to the improvement of hepatic lipid metabolism after empagliflozin administration. Decreased circulating levels of fetuin-A improved lipid metabolism and attenuated insulin resistance in the liver and in peripheral tissues. Our results highlight the beneficial effect of empagliflozin on hepatic lipid metabolism and lipid accumulation independent of obesity, with the mechanisms understood to involve decreased lipogenesis, alterations in cytochrome P450 proteins, and decreased fetuin-A. These changes help to alleviate NAFLD symptoms in the early phase of the disease and before the onset of diabetes.

The fixed-ratio combination (FRC) of a basal insulin and a GLP-1 receptor agonist (GLP-1 RA) has proven to be an effective therapeutic approach. However, physicians face numerous practical questions that cannot be answered by recently published trial results, current guidelines and summaries of product characteristics. In April 2019, a scientific meeting was held with the participation of nine experts from four Central and Eastern European countries to provide expert consensus on the optimal daily use of the insulin glargine and lixisenatide FRC (iGlarLixi). Topics included the positioning and initiation of iGlarLixi and the management of treatment. This paper summarizes the outcomes of the meeting.

This report presents the efficacy and safety of insulin degludec/liraglutide (IDegLira) versus insulin glargine 100 units/mL (IGlar U100) as initial injectable therapy at 26 weeks in the 104‐week DUAL VIII durability trial (NCT02501161). Participants (N = 1012) with type 2 diabetes (T2D) uncontrolled on oral antidiabetic drugs (OADs) were randomized 1:1 to open‐label IDegLira or IGlar U100. Visits were scheduled at weeks 1, 2, 4 and 12, and every 3 months thereafter. After 26 weeks, glycated haemoglobin (HbA1c) reductions were greater with IDegLira versus IGlar U100 (−21.5 vs. –16.4 mmol/mol [−2.0 vs. –1.5%]), as was the percentage of participants achieving HbA1c

The insulin-like growth factor (IGF) is involved in the regulation of growth and metabolism. The aim of this study was to determine selected parameters of IGF system at systemic and local levels [subcutaneous (SAT) and visceral adipose tissue (VAT)] to assess its possible role in gestational diabetes mellitus (GDM). 37 pregnant women (21 with GDM and 16 without GDM) and 15 age-matched non-pregnant females were included in the study. Blood samples were taken in 28-32 and 36-38 weeks of gestation and 6-12 months after delivery. SAT and VAT samples were obtained during delivery or surgery. Compared with non-pregnant women, serum IGF-1 and IGFBP-3 were increased in both groups of pregnant women. IGF-2 was elevated only in GDM women from 36 weeks of gestation culminating 6 months after delivery (p=0.003). Serum IGFBP-3 was increased and IGFBP-4 decreased in GDM women vs. pregnant women without GDM during the whole study (IGFBP-3: p˂0.001 for GDM vs. non-GDM; IGFBP-4: p=0.004 for GDM vs. non-GDM). Pregnant women with GDM had decreased mRNA expression of IGF-1, IGF-1R and IGF-2R and IGFBP-4 in VAT and IGF-1R in SAT compared to pregnant women without GDM. Changes in local activity of IGF are associated with the development of GDM.

The aim of our study was to assess the presence and degree of intestinal leakage in subjects suffering from short bowel syndrome (SBS) and its modification by parenteral nutrition. To this end we assessed circulating levels of selected makers of intestinal permeability including zonulin, fatty acid binding protein 2 (FABP-2), citrulline and glucagon-like peptide 2 (GLP-2). We also measured lipopolysaccharide binding protein (LBP) as a marker of circulating levels of lipopolysaccharide acting through the CD14 molecule. Eleven SBS and 10 age- and BMI-matched control subjects were included into the study. The effect of parenteral nutrition was assessed after 14 days, 6 and 12 months from its initiation, respectively. At baseline, SBS patients had increased gut permeability as measured by zonulin (47.24±2.14 vs. 39.48±1.20 ng/ml, p=0.006) and LBP (30.32±13.25 vs. 9.77±0.71 µg/ml, p

Purpose Cushing's syndrome is characterized by metabolic disturbances including insulin resistance. Mitochondrial dysfunction is one pathogenic factor in the development of insulin resistance in patients with obesity. We explored whether mitochondrial dysfunction correlates with insulin resistance and other metabolic complications. Patients and methods We investigated the changes of mRNA expression of genes encoding selected subunits of oxidative phosphorylation system (OXPHOS), pyruvate dehydrogenase (PDH) and citrate synthase (CS) in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) and mitochondrial enzyme activity in platelets of 24 patients with active Cushing's syndrome and in 9 of them after successful treatment and 22 healthy control subjects. Results Patients with active Cushing's syndrome had significantly increased body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR) and serum lipids relative to the control group. The expression of all investigated genes for selected mitochondrial proteins was decreased in SCAT in patients with active Cushing's syndrome and remained decreased after successful treatment. The expression of most tested genes in SCAT correlated inversely with BMI and HOMA-IR. The expression of genes encoding selected OXPHOS subunits and CS was increased in PM in patients with active Cushing's syndrome with a tendency to decrease toward normal levels after cure. Patients with active Cushing's syndrome showed increased enzyme activity of complex I (NQR) in platelets. Conclusion Mitochondrial function in SCAT in patients with Cushing's syndrome is impaired and only slightly affected by its treatment which may reflect ongoing metabolic disturbances even after successful treatment of Cushing's syndrome.

OBJECTIVE This trial compared the efficacy and safety of the first oral glucagon-like peptide 1 (GLP-1) receptor agonist, oral semaglutide, as monotherapy with placebo in patients with type 2 diabetes managed by diet and exercise alone. Two estimands addressed two efficacy-related questions: a treatment policy estimand (regardless of trial product discontinuation or rescue medication use) and a trial product estimand (on trial product without rescue medication use) in all randomized patients. RESEARCH DESIGN AND METHODS This was a 26-week, phase 3a, randomized, double-blind, placebo-controlled, parallel-group trial conducted in 93 sites in nine countries. Adults with type 2 diabetes insufficiently controlled with diet and exercise were randomized (1:1:1:1) to once-daily oral semaglutide 3 mg, 7 mg, 14 mg, or placebo. The primary end point was change from baseline to week 26 in HbA1c. The confirmatory secondary end point was change from baseline to week 26 in body weight. RESULTS In the 703 patients randomized (mean age 55 years, 50.8% male, and mean baseline HbA1c 8.0% [64 mmol/mol]), oral semaglutide reduced HbA1c (placebo-adjusted treatment differences at week 26: treatment policy estimand, −0.6% [3 mg], −0.9% [7 mg], and −1.1% [14 mg]; trial product estimand, −0.7% [3 mg], −1.2% [7 mg], and −1.4% [14 mg]; P < 0.001 for all) and body weight (treatment policy, −0.1 kg [3 mg], −0.9 kg [7 mg], and −2.3 kg [14 mg, P < 0.001]; trial product, −0.2 kg [3 mg], −1.0 kg [7 mg, P = 0.01], and −2.6 kg [14 mg, P < 0.001]). Mild-to-moderate transient gastrointestinal events were the most common adverse events with oral semaglutide. Trial product discontinuations occurred in 2.3–7.4% with oral semaglutide and 2.2% with placebo. CONCLUSIONS In patients with type 2 diabetes, oral semaglutide monotherapy demonstrated superior and clinically relevant improvements in HbA1c (all doses) and body weight loss (14 mg dose) versus placebo, with a safety profile consistent with other GLP-1 receptor agonists.

Nicotinamide phosphoribosyltransferase (NAMPT) is located in both the nucleus and cytoplasm and has multiple biological functions including catalyzing the rate-limiting step in NAD synthesis. Moreover, up-regulated NAMPT expression has been observed in many cancers. However, the determinants and regulation of NAMPT's nuclear transport are not known. Here, we constructed a GFP–NAMPT fusion protein to study NAMPT's subcellular trafficking. We observed that in unsynchronized 3T3-L1 preadipocytes, 25% of cells had higher GFP–NAMPT fluorescence in the cytoplasm, and 62% had higher GFP–NAMPT fluorescence in the nucleus. In HepG2 hepatocytes, 6% of cells had higher GFP–NAMPT fluorescence in the cytoplasm, and 84% had higher GFP–NAMPT fluorescence in the nucleus. In both 3T3-L1 and HepG2 cells, GFP–NAMPT was excluded from the nucleus immediately after mitosis and migrated back into it as the cell cycle progressed. In HepG2 cells, endogenous, untagged NAMPT displayed similar changes with the cell cycle, and in nonmitotic cells, GFP–NAMPT accumulated in the nucleus. Similarly, genotoxic, oxidative, or dicarbonyl stress also caused nuclear NAMPT localization. These interventions also increased poly(ADP-ribosyl) polymerase and sirtuin activity, suggesting an increased cellular demand for NAD. We identified a nuclear localization signal in NAMPT and amino acid substitution in this sequence ((424)RSKK to ASGA), which did not affect its enzymatic activity, blocked nuclear NAMPT transport, slowed cell growth, and increased histone H(3) acetylation. These results suggest that NAMPT is transported into the nucleus where it presumably increases NAD synthesis required for cell proliferation. We conclude that specific inhibition of NAMPT transport into the nucleus might be a potential avenue for managing cancer.

Immune cells are an inseparable component of adipose tissue intimately involved in most of its functions. Physiologically, they regulate adipose tissue homeostasis, while in case of adipose tissue stress, immune cells are able to change their phenotype, enhance their count and subsequently contribute to the development and maintenance of local adipose tissue inflammation. Immune cells are an important source of inflammatory cytokines and other pro-inflammatory products that further influence not only surrounding tissues but via systemic circulation also the whole organism being thus one of the main factors responsible for the transition from simple obesity to associated metabolic and cardiovascular complications. The purpose of this review is to summarize current knowledge on different adipose tissue immune cell subsets and their role in the development of obesity, type 2 diabetes mellitus and cardiovascular diseases.

(1) Background: empagliflozin, sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is an effective antidiabetic agent with strong cardio- and nephroprotective properties. The mechanisms behind its cardio- and nephroprotection are still not fully clarified. (2) Methods: we used male hereditary hypertriglyceridemic (hHTG) rats, a non-obese model of dyslipidaemia, insulin resistance, and endothelial dysfunction fed standard diet with or without empagliflozin for six weeks to explore the molecular mechanisms of empagliflozin effects. Nuclear magnetic resonance (NMR)-based metabolomics, quantitative PCR of relevant genes involved in lipid and glucose metabolism, or senescence, glucose and palmitic acid oxidation in isolated tissues and cell lines of adipocytes and hepatocytes were used. (3) Results: empagliflozin inhibited weight gain and decreased adipose tissue weight, fasting blood glucose, and triglycerides and increased HDL-cholesterol. It also improved insulin sensitivity in white fat. NMR spectroscopy identified higher plasma concentrations of ketone bodies, ketogenic amino acid leucine and decreased levels of pyruvate and alanine. In the liver, adipose tissue and kidney, empagliflozin up-regulated expression of genes involved in gluconeogenesis and down-regulated expression of genes involved in lipogenesis along with reduction of markers of inflammation, oxidative stress and cell senescence. (4) Conclusion: multiple positive effects of empagliflozin, including reduced cell senescence and oxidative stress, could contribute to its long-term cardio- and nephroprotective actions.

Diabetes represents the leading risk factor for the development of cardiovascular disease (CVD). Chronic hyperglycemia and/or acute post-prandial changes in blood glucose determine an increase in reactive oxygen species (ROS), which play a fundamental role in endothelial dysfunction and in the nuclear transport of pro-atherogenic transcription factors that activate the "inflammasome". In addition, the glycemic alteration favors the formation and stabilization of atherosclerotic plaque through the mechanism of non-enzymatic glycation of different molecules, with the establishment of the so-called "advanced glycosylation end products" (AGE). Laboratory information provided by the level of biomarkers could make a quantitative and qualitative contribution to the clinical process of screening, prediction, prevention, diagnosis, prognosis and monitoring of cardiovascular (CV) risk linked to diabetes. This review describes the importance of specific biomarkers, with particular focus on novel ones, for stratifying and management of diabetes CV risk.

Cellular senescence is a novel mechanism suggested to contribute to the development of type 2 diabetes mellitus (T2DM) and cardiovascular diseases. Here, we analyzed the expression of senescent markers in myocardium and adjacent adipose tissue of subjects with and without coronary artery disease (CAD) and T2DM undergoing elective cardiac surgery. Eleven subjects with CAD and T2DM (DM group), 13 subjects with CAD without T2DM (CAD group) and 8 subjects without both CAD and T2DM (C - control) group undergoing elective cardiac surgery (CABG and/or valvular surgery) were included into the study. Samples of subcutaneous (SAT) and epicardial (EAT) adipose tissue and myocardium form right atrial wall were taken along with standard biochemical and anthropometric parameters at the beginning and end of surgery. mRNA expression of senescent markers p21 and p16 was assessed using qRT PCR. All 3 groups did not differ with respect to age (65.2 ± 6.9 vs. 61.7 ± 9.8 vs. 57.9 ± 12.3 years for DM vs. CAD vs. C, n.s.) or BMI (30.8 ± 3.9 vs. 28.5 ± 3.9 vs. 30.2 ± 3.4 kg/m2, n.s.), while DM group showed higher levels of fasting glucose (8.4 ± 1.6 vs. 5.9 ± 1.1 vs. 5.9 ± 0.9 mmol/, p=0.005) and HbA1C (52.5 ± 8.9 vs. 38.9 ± 4.2 vs. 31.5 ± 8.9 mmol/mol, p Disclosure M. Mraz: None. M. Haluzik: Advisory Panel; Self; AstraZeneca, Lilly Diabetes, Novo Nordisk, Consultant; Self; Sanofi. J. Trnovska: None. B. Kasperova: None. I. Dvorakova: None. Z. Lacinova: None. D. Hlavacek: None. J. Mahrik: None. P. Ivak: None. I. Netuka: None. Funding Ministry of Health of the Czech Republic (RVO-VFN64165, NV19-0200118); IKEM (IN00023001)

Gestational diabetes mellitus (GDM) is diabetes that is first diagnosed in the second or third trimester of pregnancy in patients who did not have a history of diabetes before pregnancy. Consequences of GDM include increased risk of macrosomia and birth complications in the infant and an increased risk of maternal type 2 diabetes mellitus (T2DM) after pregnancy. There is also a longer-term risk of obesity, T2DM, and cardiovascular diseases in the child. GDM is the result of impaired glucose tolerance due to pancreatic β-cell dysfunction on a background of insulin resistance that physiologically increases during pregnancy. The strongest clinical predictors of GDM are overweight and obesity. The fact that women with GDM are more likely to be overweight or obese suggests that adipose tissue dysfunction may be involved in the pathogenesis of GDM, similarly to T2DM. Adipose tissue is not only involved in energy storage but also functions as an active endocrine organ secreting adipokines (specific hormones and cytokines) with the ability to alter insulin sensitivity. Recent evidence points to a crucial role of numerous adipokines produced by fat in the development of GDM. The following text summarizes the current knowledge about a possible role of selected adipokines in the development of GDM.

(1) Background: The influence of ketogenic diet on physical fitness remains controversial. We performed a randomized controlled trial to compare the effect of cyclical ketogenic reduction diet (CKD) vs. nutritionally balanced reduction diet (RD) on body composition, muscle strength, and endurance performance. (2) Methods: 25 healthy young males undergoing regular resistance training combined with aerobic training were randomized to CKD (n = 13) or RD (n = 12). Body composition, muscle strength and spiroergometric parameters were measured at baseline and after eight weeks of intervention. (3) Results: Both CKD and RD decreased body weight, body fat, and BMI. Lean body mass and body water decreased in CKD and did not significantly change in RD group. Muscle strength parameters were not affected in CKD while in RD group lat pull-down and leg press values increased. Similarly, endurance performance was not changed in CKD group while in RD group peak workload and peak oxygen uptake increased. (4) Conclusions: Our data show that in healthy young males undergoing resistance and aerobic training comparable weight reduction were achieved by CKD and RD. In RD group, improved muscle strength and endurance performance was noted relative to neutral effect of CKD that also slightly reduced lean body mass.

Coronary artery disease is one of the most frequent causes of morbidity and mortality worldwide. It is even more prevalent in patients with type 2 diabetes mellitus who suffer from obesity and increased accumulation of epicardial fat with a possible contributing role in the development of coronary artery disease. We performed an MS-based lipidomic analysis of subcutaneous and epicardial adipose tissue in 23 patients with coronary artery disease stratified for the presence/absence of type 2 diabetes mellitus and a control group of 13 subjects aiming at identification of factors from epicardial fat contributing to the development of coronary artery disease. The samples of adipose tissues were obtained during elective cardiac surgery. They were extracted and analyzed with and without previous triacylglycerols separation by high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Multi-variate and univariate analyses were performed. Lipidomics data were correlated with biochemical parameters. We identified multiple changes in monoacylglycerols, diacylglycerols, triacylglycerols, glycerophosphatidylserines, glycerophosphatidylethanolamines, glycerophosphatidylcholines, ceramides, sphingomyelins, and derivatives of cholesterol. Observed changes included molecules with fatty acids with odd (15:0, 15:1, 17:0, 17:1) and even (10:0, 12:0, 14:0, 16:0, 16:1, 18:0, 18:1, 18:2, 20:4, 20:1, 22:0) fatty acids in both types of adipose tissue. More pronounced changes were detected in epicardial adipose tissue compared to subcutaneous adipose tissue of patients with coronary artery disease and type 2 diabetes. Lipidomic analysis of subcutaneous and epicardial adipose tissue revealed different profiles for patients with coronary artery disease and type 2 diabetes, which might be related to coronary artery disease and the presence of type 2 diabetes.

Type 2 diabetes mellitus represents a major health problem with increasing prevalence worldwide. Limited efficacy of current therapies has prompted a search for novel therapeutic options. Here we show that treatment of pre-diabetic mice with mitochondrially targeted tamoxifen, a potential anti-cancer agent with senolytic activity, improves glucose tolerance and reduces body weight with most pronounced reduction of visceral adipose tissue due to reduced food intake, suppressed adipogenesis and elimination of senescent cells. Glucose-lowering effect of mitochondrially targeted tamoxifen is linked to improvement of type 2 diabetes mellitus-related hormones profile and is accompanied by reduced lipid accumulation in liver. Lower senescent cell burden in various tissues, as well as its inhibitory effect on pre-adipocyte differentiation, results in lower level of circulating inflammatory mediators that typically enhance metabolic dysfunction. Targeting senescence with mitochodrially targeted tamoxifen thus represents an approach to the treatment of type 2 diabetes mellitus and its related comorbidities, promising a complex impact on senescence-related pathologies in aging population of patients with type 2 diabetes mellitus with potential translation into the clinic.

Aims: Evidence from cardiovascular outcomes trials (CVOTs) of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors was reflected in the most recent guidelines from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). The aim of the present study was to assess the adoption of the ADA/EASD guidelines in a convenience sample of physicians from Eastern and Southern Europe, the barriers to the implementation of these guidelines and the measures needed to facilitate their implementation. Methods: Attendees at two international diabetes conferences could volunteer to respond to a fully anonymous survey. Responses were analysed descriptively and a panel of experts from around the region was consulted to interpret the survey results. Results: Responses (n = 96) from 10 countries were analysed. Most participants (63.4%) considered the ADA/EASD guidelines fundamental to their practice. All respondents saw the value of the CVOT-based ADA/EASD recommendations and 77-80% generally implemented them. Measures suggested to improve adherence to the ADA/EASD guidelines included aligning reimbursement policy with the guidelines (54.4%), publishing guidelines in a simple and concise form (42.4%) and translating guidelines into local languages (33.3%). Conclusions: Aligning reimbursement with recent evidence and providing short summaries of the ADA/EASD guidelines in local languages could facilitate physician adherence.(c) 2020 The Author. Published by Elsevier B.V. This is an open access article under the CC BY NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Context Neudesin has recently been identified as a novel regulator of energy expenditure in experimental animals; however, its role in humans remains unexplored. Objective The aim of this study was to assess the effects of obesity and type 2 diabetes mellitus (T2DM) along with selected weight reducing interventions on serum neudesin levels and adipose tissue mRNA expression. Patients and methods Fifteen obese subjects with T2DM undergoing endoscopic duodenal-jejunal bypass liner (DJBL) implantation, 17 obese subjects (11 with T2DM, 6 without T2DM) scheduled for gastric plication (GP), 15 subjects with functional hypoglycemia subjected to 72-hour acute fasting (AF), and 12 healthy controls were included in the study. Results Baseline neudesin levels were comparable between all groups. DJBL increased neudesin at 6 and 10 months after the procedure (1.77±0.86 vs 2.28±1.27 vs 2.13±1.02 ng/mL, P=0.001 for baseline vs 6 vs 10 months) along with reduction in body weight and improvement of HbA1c without any effect on neudesin mRNA expression in subcutaneous adipose tissue. Conversely, GP did not affect neudesin levels despite marked reduction in body weight and improvement of HbA1c. In contrast, AF decreased neudesin levels during the entire period (1.74±0.54 vs 1.46±0.48 ng/mL, P=0.001 for baseline vs 72 hours) with no impact of subsequent re-alimentation on neudesin concentrations. Conclusion Neudesin levels are differentially regulated during AF and chronic weight reduction induced by DJBL or GP. Further studies are needed to assess its possible significance in energy homeostasis regulation in humans.

Obesity and associated metabolic complications are established risk factors for the development and progression of chronic kidney disease; however, BMI (body mass index)>35 kg/m2 is a contraindication for kidney transplantation. The aim of our study was to reduce excess body weight via laparoscopic sleeve gastrectomy (LSG) in obese patients with end-stage renal disease (ESRD) in order for them to become eligible for the transplantation program. Subjects with ESRD undergoing hemodialysis or peritoneal dialysis and BMI>35kg/m2 without serious comorbidities were included into the study. Anthropometric and biochemical parameters were measured before and 1, 3 and 6 months after LSG. In the thus far enrolled 7 subjects (6 females, aged 47.6 ± 9.6 years) LSG resulted in improved body weight (118.0 ± 17.6 vs. 107.5 ± 14.5 vs. 105.5 ± 14.4 vs. 99.5 ± 10.7 kg for baseline vs. 1 vs. 3 vs. 6 months, p To conclude, our pilot data suggest LSG to be an efficient and safe method to achieve the necessary weight reduction enabling renal transplantation in subjects with renal failure and higher degrees of obesity. Disclosure V. Hrádková: None. M. Kasalicky: None. S. Rajnochova-Bloudickova: None. I. Lankova: None. H. Kratochvilova: None. M. Mraz: None. K. Dvorakova: None. S. Slaba: None. J. Mendl: None. O. Viklicky: None. J. Fronek: None. M. Haluzik: Advisory Panel; Self; Lilly Diabetes, Sanofi. Consultant; Self; Ethicon US, LLC. Speaker’s Bureau; Self; AstraZeneca, Mundipharma International, Novartis AG, Novo Nordisk A/S. Funding Institute for Clinical and Experimental Medicine (00023001)

Diabetes and ageing are mutually linked and senescent cells might be involved in the development of obesity and type 2 diabetes mellitus (T2DM). Recent studies have shown that senolytic agents may improve diabetes-related pathologies. To this end we have tested our novel anti-cancer agent with senolytic properties, mitochondrially targeted tamoxifen (MitoTam), in a mouse model of T2DM. Obesity and diabetic metabolic profile were induced by high fat diet (HFD) feeding in 20 C57BL/6J male mice for 6 months with another group fed a standard diet (SD) serving as controls. Subsequently, both groups were divided into 2 subgroups (n=10 each) treated either with MitoTam (2µg/1g of body weight dissolved in 4% ethanol in corn oil) or the excipient given i.p. twice a week for a period of 4 weeks. In HFD animals, MitoTam decreased body weight already after 2 weeks of treatment, with most pronounced reduction of visceral adipose tissue (VAT, P In conclusion, our results suggest that MitoTam significantly improves HFD-induced obesity and diabetes in mice and that this effect might be in part mediated by alleviated senescence in adipose tissue. Disclosure J. Trnovska: None. E. Davidova: None. P. Svoboda: None. H. Kratochvilova: None. M. Mraz: None. S. Hubackova: None. J. Neuzil: None. M. Haluzik: Advisory Panel; Self; Lilly Diabetes, Sanofi. Consultant; Self; Ethicon US, LLC. Speaker’s Bureau; Self; AstraZeneca, Mundipharma International, Novartis AG, Novo Nordisk A/S. Funding Institute for Clinical and Experimental Medicine (00023001); Czech Science Foundation (GA 18-02550S)

The global PIONEER program investigated the efficacy and safety of the first oral glucagon-like peptide-1 receptor agonist, oral semaglutide. Across PIONEER trials, patients with type 2 diabetes (T2D) were randomized to once-daily oral semaglutide (3, 7, 14 mg or flexibly dosed) or comparator. The present exploratory subgroup analysis evaluated the effect of background medications on glycated hemoglobin (HbA1c) and body weight (BW) reductions at the end of trial (week 26, 52 or 78) in five PIONEER trials (3-5, 7-8). Data were analyzed from patients who received oral semaglutide or comparator (sitagliptin, liraglutide or placebo) based on background medication received: metformin, sulfonylurea, sodium-glucose co-transporter 2 inhibitor, insulin or combinations. Baseline characteristics were generally similar across subgroups. Reductions in HbA1c and BW were greater for oral semaglutide vs. comparators (except liraglutide, with similar HbA1c reductions), regardless of background medication (Table). In general, there were no statistically significant interactions between treatment and subgroups. Estimated treatment differences were consistent within each trial and background medication subgroups. These findings support the use of oral semaglutide across a broad population of patients with T2D in combination with other commonly used glucose-lowering agents. Disclosure J.B. Buse: Consultant; Self; Cirius Therapeutics, CSL Behring, Neurimmune. Research Support; Self; American Diabetes Association, National Institutes of Health, Novo Nordisk A/S, Patient-Centered Outcomes Research Institute, Sanofi, Tolerion, Inc., vTv Therapeutics. Stock/Shareholder; Self; Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Stability Health. Other Relationship; Self; ADOCIA, AstraZeneca, Dance Biopharm Holdings, Inc., Eli Lilly and Company, MannKind Corporation, NovaTarg Therapeutics, Novo Nordisk A/S, Senseonics, Inc, vTv Therapeutics, Zafgen, Inc. M. Crowley: None. J.W. Eriksson: Advisory Panel; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. M. Gislum: Employee; Self; Novo Nordisk A/S. C.L. Hertz: Employee; Self; Novo Nordisk A/S. M. Kaiser: Advisory Panel; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Lilly Diabetes. A. Moeller Nielsen: Employee; Self; Novo Nordisk A/S. M. Haluzik: Advisory Panel; Self; Lilly Diabetes, Sanofi. Consultant; Self; Ethicon US, LLC. Speaker’s Bureau; Self; AstraZeneca, Mundipharma International, Novartis AG, Novo Nordisk A/S. Funding Novo Nordisk A/S