The emergence of multi-drug-resistant bacteria causing healthcare-associated infections in COVID-19 patients: a retrospective multi-centre study.

INTRODUCTION: We evaluated the prevalence, aetiologies and antibiotic resistance patterns of bacterial infections in hospitalized patients with laboratory-confirmed SARS-CoV-2. We also investigated comorbidities, risk factors and the mortality rate in COVID-19 patients with bacterial infections. METHODS: This retrospective observational study evaluated medical records of 7249 randomly selected patients with COVID-19 admitted to three clinical centres between 1st January 2021 and 16th February 2022. A total of 6478 COVID-19 patients met the eligibility criteria for analysis. RESULTS: The mean age of the patients with SARS-CoV-2 and bacterial infections was 68.6 ± 15.5 years (range: 24-94 years). The majority of patients (68.7%) were older than 65 years. The prevalence of bacterial infections among hospitalized COVID-19 patients was 12.9%, most of them being hospital-acquired (11.5%). Bloodstream (37.7%) and respiratory tract infections (25.6%) were the most common bacterial infections. Klebsiella pneumoniae and Acinetobacter baumannii caused 25.2% and 23.6% of all bacterial infections, respectively. Carbapenem-resistance in Enterobacterales, A. baumannii and Pseudomonas aeruginosa were 71.3%, 93.8% and 69.1%, respectively. Age >60 years and infections caused by ≥3 pathogens were significantly more prevalent among deceased patients compared with survivors (P<0.05). Furthermore, 95% of patients who were intubated developed ventilator-associated pneumonia. The overall in-hospital mortality rate of patients with SARS-CoV-2 and bacterial infections was 51.6%, while 91.7% of patients who required invasive mechanical ventilation died. CONCLUSIONS: Our results reveal a striking association between healthcare-associated bacterial infections as an important complication of COVID-19 and fatal outcomes.

WHAT IS STRESS HYPERGLYCEMIA? A SUGGESTION FOR AN IMPROVEMENT OF ITS DEFINITION.

Context: Stress hyperglycemia has been studied in numerous critical illnesses for several decades. Despite the extensive accumulation of knowledge about this topic, the definition of stress hyperglycemia is not updated since 2007. Subjects and Methods: We performed a narrative review about stress hyperglycemia in acute myocardial infarction (AMI), aiming to improve its current definition and to give evidence supporting this. Results: The definition of stress hyperglycemia in 2021 we recommend is: "SH is a high ABGly in an AMI patient irrespective of DM status. It can be calculated as e.g., "stress hyperglycemia ratio" or "admission glucose delta"/"glycemic gap". This definition may serve to start a consensus document of the experts in the field. The evidence accumulates supporting the possibility to recognize stress hyperglycemia also in AMI patients with diabetes mellitus (DM) by calculating glycemia during the previous 2-3 months using glycated hemoglobin. Moreover, it is now obvious that 2007 definition of stress hyperglycemia did not take into account the necessity to separate cut-offs for the subgroups with vs. without DM. Conclusions: We demonstrated the insufficiency of the current 2007 definition of stress hyperglycemia, provided evidence-based recommendation for the improvement and suggested the need for a consensus of the experts on this topic. In order to optimize the treatment of stress hyperglycemia in numerous critical illnesses, we ought to have its universal definition (as we already have the universal definition of AMI).

Liver anatomy, intrahepatic vascular and biliary branching system of the mole rat (Spalax leucodon).

BACKGROUND: There are many studies on the morphology of the liver and its blood vessels in experimental animals, but such studies are lacking in the mole rat (Spalax leucodon). The aim of this paper was a detailed basic study on the topography, morphology, vascular and biliary branching systems of the liver in the mole rat. MATERIALS AND METHODS: Coloured gelatine and mixture of coloured lead oxide and linseed oil were injection contrast masses used to obtain vascular and biliary branching pattern in the liver. It was revealed that the liver of the mole rat had five lobes (left, quadrate, right medial, right lateral and caudate lobes). RESULTS: The left, undivided lobe was the largest lobe of the liver. The quadrate lobe was divided into two components by a deep notch. The gallbladder, of cylindrical shape, was present and attached to the quadrate lobe. The common bile duct was formed by the union of the left and right hepatic ducts. The pancreatic duct joined the common bile duct before it entered the duodenum. In the present study, only the right medial lobe and quadrate lobe always showed a single lobar artery, portal and hepatic veins. The left lobe showed four lobar arteries, portal and hepatic veins. The caudate lobe with its two processes and the right lateral and medial lobes had different arterial and portal blood supply as well as hepatic and biliary drainage of these lobes. The intrahepatic branches of the proper hepatic artery ran parallel to the branches of the common portal vein in the same lobes of the liver. CONCLUSIONS: The results of this study are significant for comparative studies among different species of rodents and other experimental animals. Morphology, vasculature and biliary tract of the liver in the mole rat were similar to that of other experimental animals and identified differences may be related to the adaptation to the mode of life and diet of this rodent.

High likelihood for atrial fibrillation in Cushing's syndrome.

OBJECTIVE: This review analyzes the prevalence of the most important comorbidities associated with atrial fibrillation (AF) in the growing population of patients with Cushing's syndrome (CS). MATERIALS AND METHODS: The review is arranged in a way to list important risk factors for AF and the references, which suggest the significant prevalence of these particular risk factors in CS. The search is conducted on PubMed, Science Direct, Springer, Wiley, SAGE, Oxford Press, and Google Scholar. PubMed search for "Cushing's syndrome atrial fibrillation" on 8/7/2019 revealed 4 papers only. None of them either analyzed or implicated high risk for AF in CS. RESULTS: Arterial hypertension (AHT) can be found in approximately 80% of adult individuals with endogenous CS and in 20% of patients with exogenous CS. The reported prevalence of diabetes mellitus (DM) is from 13% to 47% in CS patients and the risk for de novo DM is approximately two-fold higher in individuals treated with glucocorticoids. High risk for myocardial infarction (MI) with hazard ratio (HR) 3.7 (95% confidence intervals, CI 2.4-5) in patients with endogenous CS was found. In CS patients the obesity can be detected in up to 41% and overweight in 21-48%. Left ventricular hypertrophy (LVH), pulmonary thromboembolism (PTE), infections, and hypokalemia are also more prevalent in CS as compared to healthy population. All cited comorbidities have been associated with AF. Therefore, clustering of the important factors associated with AF is confirmed repeatedly in CS. CONCLUSIONS: The prevalence of AF in CS should be studied more precisely, both in a scientific way and at the individual patient's level.

Double trouble: myocardial infarction with non-obstructive coronary arteries as a presentation of Hughes syndrome in monozygotic twins.

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a recently described, clinically significant entity, with prevalence rates ranging from 1% to 14% and a mean of 6% of all patients with myocardial infarction. Antiphospholipid syndrome (APS; Hughes syndrome) is characterized by the presence of antiphospholipid antibodies associated with thrombosis (arterial and/or venous) and/or pregnancy morbidity and could be the cause of MINOCA. Data on genetic predisposition to APS are scarce. The present study describes a unique case of monozygotic twin brothers who, at a young age, developed the same clinical presentation of APS. The diagnosis of APS was later confirmed, along with a diagnosis of systemic lupus erythematosus in one brother.

An international survey about rapid sequence intubation of 10,003 anaesthetists and 16 airway experts.

Pulmonary aspiration of gastric content is a significant cause of anaesthesia-related morbidity and mortality. High-quality prospective randomised evidence to support prevention strategies, such as rapid sequence intubation, is difficult to generate due to well-described practical, ethical and methodological barriers. We aimed to generate an understanding of worldwide practice through surveying clinically practicing anaesthetists and airway experts. Our survey was designed to assess the influence of: departmental standards; patient factors; socio-economic factors; training; and supervision. We surveyed 10,003 anaesthetists who responded to an invitation to participate on LinkedIn. We then surveyed 16 international airway experts on the same content. When asked about a hypothetical patient with intestinal obstruction, respondents expressed preferences for [OR (95%CI)]: the head-up or -down position 4.26 (3.98-4.55), p < 0.001; nasogastric tube insertion 29.5 (26.9-32.3), p < 0.001; and the use of cricoid force 2.80 (2.62-3.00), p < 0.001, as compared with a hypothetical patient without intestinal obstruction also requiring rapid sequence intubation. Respondents from lower income countries were more likely to prefer [OR (95%CI]: the supine position 2.33 (2.00-2.63), p < 0.001; nasogastric tube insertion 1.29 (1.09-1.51), p = 0.002; and cricoid force application 2.54 (2.09-3.09), p < 0.001 as compared with respondents from higher income countries for a hypothetical patient with intestinal obstruction. This survey, which we believe is the largest of its kind, demonstrates that preferences for positioning, nasogastric tube use and cricoid force application during rapid sequence intubation vary substantially. Achieving agreed consensus may yield better training in the principles of rapid sequence intubation.

Usefulness of heart rate recovery parameters to monitor cardiovascular adaptation in elite athletes: The impact of the type of sport.

PURPOSE: The purpose of this study is to determine heart rate (HR) recovery after maximal test in elite athletes who compete in high dynamic, high static, and in mixed sport disciplines; to assess differences in HR recovery between these groups of athletes; and to measure the association of HR index (HRI) with heart adaptation variables to determine whether these values were correlated with the type of exercise. METHODS: One hundred and ninety-four elite athletes were divided into three groups according to the predominant type of exercise performed: endurance (n = 40), strength-sprinter (n = 36), and ball-game players (n = 118). They performed maximal cardiopulmonary exercise testing on a treadmill and were subjected to echocardiography. The rate of decline (HR recovery) was calculated as the difference between maximum and recovery HRs (HRrec1 and HRrec3). The HRI was calculated as HRmax - 1-min post-exercise HR (HRrec1). RESULTS: The most significant correlation of HRI was with posterior wall diameter and left ventricular (LV) mass index (r = 0.43 and r = 0.51; p = 0.012 and p = 0.003, respectively). LV mass index [Beta (B) = 0.354, p = 0.001] was an independent predictor of HRI and HRrec1. HRI may be an effective tool for discrimination of physiological and "gray zone" LV hypertrophy, with area under the curve of 0.545 (95% CI = 0.421-0.669, p = 0.0432). HRI displayed a sensitivity of 50% and specificity of 52.2% at the optimal cut-off value of 23.5. CONCLUSION: HR recovery pattern, especially HRI, may offer a timely and efficient tool to identify athletes with autonomous nervous system adaptive changes.

The cutaneous manifestations are significantly related to cerebrovascular in a Serbian cohort of patients with Hughes syndrome.

Objectives To investigate a possible relationship between cerebrovascular, such as stroke and transient ischaemic attack, and various cutaneous manifestations (livedo reticularis, skin ulcerations, pseudovasculitis lesions, superficial cutaneous necrosis and digital gangrene) in antiphospholipid syndrome (APS). This report is based on a Serbian cohort of APS patients. Methods A total of 508 antiphospholipid syndrome APS patients were assessed: 360 with primary (PAPS) and 148 with APS associated with SLE (SAPS). Antiphospholipid antibodies analysis included detection of anti-cardiolipin (IgG/IgM), anti-ß2glycoprotein I (IgG/IgM) and positive lupus anticoagulant test. Results The prevalence of cutaneous manifestations in our cohort was significantly higher in the SAPS group (76.4% vs. 27.2%, p = 0.0001). In both groups, the most common manifestation was livedo reticularis. The majority of cutaneous manifestations were significantly associated with cerebrovascular events in SAPS and PAPS. Cutaneous manifestations were independent predictors of transient ischaemic attack and stroke in PAPS patients (odds ratio 2.850, 95% confidence interval 1.562-5.202, p = 0.001, odds ratio 1.832, 95% confidence interval 1.024-3.277, p = 0.041, respectively). Conclusion In this cross-section analysis of a large cohort of Serbian APS patients, there was a strong relationship between cutaneous and cerebrovascular manifestations, suggesting a more cautious approach regarding neurological symptoms, especially in PAPS patients with cutaneous manifestations present.

Pulse Wave Velocity: Retrospective Analysis in a Balkan Normotensive and Hypertensive Population: A Study of 9923 Patients.

We compared pulse wave velocity (PWV) between hypertensive patients and control patients to identify demographics and patient characteristics related to PWV. We retrospectively analyzed 9923 participants (3105 controls and 6818 hypertensive patients) from 5 outpatient hypertensive clinics (in Serbia and Greece). Pulse wave velocity had different distribution between controls and hypertensive patients ( P < .001). The magnitude of PWV increase was related to blood pressure (BP) category (from optimal to stage III hypertension; P < .001). Even in hypertensive patients with systolic BP (SBP) <140 and/or diastolic BP (DBP) <90 mm Hg, PWV was greater than in control patients ( P < .001). Pulse wave velocity was associated with almost all baseline characteristics of hypertensive patients (body mass index [BMI], gender, age, SBP, DBP, smoking status, and heart rate; P < .001). This association remained after adjustment of PWV confounders. There were 2231 (32.7%) hypertensive patients who had reached SBP <140 mm Hg and DBP <90 mm Hg. Pulse wave velocity was increased in hypertensive patients, and the degree of PWV increase was associated with baseline BP as well as with anthropometric parameters (eg, BMI, gender, age, heart rate, and smoking status).

Correlation between ECG changes and early left ventricular remodeling in preadolescent footballers.

The aim of this study was to assess the early electrocardiogram (ECG) changes induced by physical training in preadolescent elite footballers. This study included 94 preadolescent highly trained male footballers (FG) competing in Serbian Football League (minimum of 7 training hours/week) and 47 age-matched healthy male controls (less than 2 training hours/week) (CG). They were screened by ECG and echocardiography at a tertiary referral cardio center. Sokolow-Lyon index was used as a voltage electrocardiographic criterion for left ventricular hypertrophy diagnosis. Characteristic ECG intervals and voltage were compared and reference range was given for preadolescent footballers. Highly significant differences between FG and CG were registered in all ECG parameters: P-wave voltage (p < 0.001), S-wave (V1 or V2 lead) voltage (p < 0.001), R-wave (V5 and V6 lead) voltage (p < 0.001), ECG sum of S V1-2 + R V5-6 (p < 0.001), T-wave voltage (p < 0.001), QRS complex duration (p < 0.001), T-wave duration (p < 0.001), QTc interval duration (p < 0.001), and R/T ratio (p < 0.001). No differences were found in PQ interval duration between these two groups (p > 0.05). During 6-year follow-up period, there was no adverse cardiac event in these footballers. None of them expressed pathological ECG changes. Benign ECG changes are presented in the early stage of athlete's heart remodeling, but they are not related to pathological ECG changes and they should be regarded as ECG pattern of LV remodeling.

Dianthus barbatus-A New Host of Stolbur Phytoplasma in Serbia.

Sweet William (Dianthus barbatus, Caryophyllaceae) is a biennial or short-lived perennial plant native to southern Europe, from the Pyrenees to the Carpathians and the Balkans. During the summers of 2012 and 2013, phytoplasma-like symptoms were observed on D. barbatus plants on a Serbian plantation (Pancevo, 44°51'49″ N, 20°39'33″ E, 80 m ASL). Only seven symptomatic plants were observed in the summer of 2012. Disease incidence in 2013 was estimated to be less than 1% but increased during 2014 to 4%. Affected plants, showing symptoms of leaf reddening, malformation, and proliferation; flower bud deficiency; and abnormal shoot production, were tested for phytoplasmas. Samples were collected from seven symptomatic and three symptomless plants each year (20 samples), and total nucleic acid was extracted from midrib tissue using a method that includes a phytoplasma enrichment step and DNA purification by chloroform/phenol (3). Oligonucleotide primers specific to the phytoplasma 16S to 23S rRNA intergenic spacer region were used in polymerase chain reaction (PCR) assays on DNA extracted from Sweet William plants (1,3). Using phytoplasma universal primer pairs P1/P7 and P1/16S-Sr, phytoplasma-specific 1.8- and 1.5-kb amplicons were obtained from four and six symptomatic plants collected in 2012 and 2013, respectively. Nested PCR with R16F2n/R2 primers yielded ~1.2-kb amplicons from DNAs of all symptomatic plants (1). No amplicon was generated in PCRs conducted with DNA templates from symptomless plants. Restriction fragment length polymorphism (RFLP) analysis of amplified 1.2-kb fragments was performed using four endonucleases (AluI, Tru1I, HhaI, and HpaII). Comparative analysis was done using RFLP patterns of Stolbur (Stol), Aster Yellows (AY), Flavescence Doree-C (FD-C), Poinsettia Branch-Inducing (PoiBI), and Clover Yellow Edge (CYE) phytoplasmas. PCR-RFLP patterns from tested samples were identical to those of the Stol reference strain, indicating that diseased Sweet William was affected by phytoplasma belonging to the 16SrXII-A (Stolbur) group. The sequence of a 1.2-kb rDNA PCR product derived from sample Tk9 (deposited under accession number KM401436 in NCBI GenBank) showed the closest identity (100%) to those of Bulgarian corn (KF907506.1), Iranian 'Bois Noir' (KJ637208.1), and two Serbian phytoplasmas (KJ174507.1 from Calendula officinalis and KF614623.1 from Paeonia tenuifolia), all belonging to the 'Candidatus Phytoplasma solani' Stolbur subgroup. Previously, Aster Yellows Phytoplasma (16SrI) had been detected in two Dianthus species: D. barbatus (Sweet William) and D. caryophyllus (carnation) (2). This is the first record of the 16SrXII-A phytoplasma subgroup being associated with yellowing and reddening of D. barbatus in Serbia. The Stolbur phytoplasma occurrence on Sweet William is significant for the management of the disease in Serbia. References: (1) I. M. Lee et al. Int. J. Syst. Bacteriol. 48:1153, 1998. (2) P. Northover et al. http://www.umanitoba.ca/faculties/afs/MAC_proceedings/proceedings/ 2007/Philip_Northover.pdf , 2007. (3) J. P. Prince et al. Phytopathology 83:1130, 1993.

Umbilical endometriosis associated with large umbilical hernia. Case report.

Umbilical endometriosis is a rare condition, usually following laparoscopic and surgical procedures involving the umbilicus.Spontaneous umbilical endometriosis occurring without any previous abdominal or uterine surgery is extremely rare. The maximal depth of penetration of the umbilical endometriosis described is up to fascial level. There have been only two cases of endometriosis reported arising within umbilical hernia. The authors report a case of a patient with spontaneous umbilical endometriosis associated with a large umbilical hernia, treated by surgical excision and mesh repair of the abdominal wall. To the best of our knowledge, this is the first described case of the association of umbilical endometriosis with a large umbilical hernia that requires prosthetic mesh repair of the abdominal wall defect.

The First Report of Stolbur Phytoplasma Associated with Phyllody of Calendula officinalis in Serbia.

Pot marigold (Calendula officinalis L.) is native to southern Europe. Compounds of marigold flowers exhibit anti-inflammatory, anti-tumor-promoting, and cytotoxic activities (4). In Serbia, pot marigold is cultivated as an important medicinal and ornamental plant. Typical phyllody, virescence, proliferation of axillary buds, and witches' broom symptoms were sporadically observed in 2011 in Pancevo plantation, Serbia (44°51'49″ N, 20°39'33″ E, 80 m above sea level). Until 2013, the number of uniformly distributed affected pot marigold plants reached 20% in the field. Due to the lack of seed production, profitability of the cultivation was seriously affected. Leaf samples from 10 symptomatic and 4 symptomless marigold plants were collected and total nucleic acid was extracted from midrib tissue (3). Direct PCR and nested PCR were carried out with primer pairs P1/16S-SR and R16F2n/R16R2n, respectively (3). Amplicons 1.5 and 1.2 kb in length, specific for the 16S rRNA gene, were amplified in all symptomatic plants. No PCR products were obtained when DNA isolated from symptomless plants was used. Restriction fragment length polymorphism (RFLP) patterns of the 1.2-kb fragments of 16S rDNA were determined by digestion with four endonucleases separately (TruI1, AluI, HpaII, and HhaI) and compared with those of Stolbur (Stol), Aster Yellows (AY), Flavescence dorée-C (FD-C), Poinsettia Branch-Inducing (PoiBI), and Clover Yellow Edge (CYE) phytoplasmas (2). RFLP patterns from all symptomatic pot marigold plants were identical to the Stol pattern, indicating Stolbur phytoplasma presence in affected plants. The 1.2-kb amplicon of representative Nv8 strain was sequenced and the data were submitted to GenBank (accession no. KJ174507). BLASTn analysis of the sequence was compared with sequences available in GenBank, showing 100% identity with 16S rRNA gene of strains from Paeonia tenuifolia (KF614623) and corn (JQ730750) from Serbia, and peach (KF263684) from Iran. All of these are members of the 16SrXII 'Candidatus Phytoplasma solani' group, subgroup A (Stolbur). Phytoplasmas belonging to aster yellows (16SrI) (Italy and Canada) and peanut witches' broom related phytoplasma (16SrII) group (Iran) have been identified in diseased pot marigold plants (1). To our knowledge, this is the first report of natural infection of pot marigold by Stolbur phytoplasma in Serbia. References: (1) S. A. Esmailzadeh-Hosseini et al. Bull. Insectol. 64:S109, 2011. (2) I. M. Lee et al. Int. J. Syst. Bacteriol. 48:1153, 1998. (3) J. P. Prince. Phytopathology 83:1130, 1993. (4) M. Ukiya et al. J. Nat. Prod. 69:1692, 2006.

Correlation of nuclear morphometry of primary melanoma of the skin with clinicopathological parameters and expression of tumor suppressor proteins (p53 and p16(INK4a)) and bcl-2 oncoprotein.

PURPOSE: To determine the correlation of nuclear morphometry of primary cutaneous malignant melanoma (CMM) with clinicopathological parameters and the expression of p53, p16INK4a, and bcl-2. METHODS: Image analysis and computerized nuclear morphometry were used in a series of 53 primary CMM (nodular melanoma/NM, N=33, and superficially spreading melanoma/SSM, N=20). The clinicopathological parameters determined for each tumor were histological type, maximal tumor diameter, Breslow thickness, Clark level, ulceration, mitotic index (MI) and pathological disease stage. Measured nuclear features included size, shape and optical density (OD). The results were correlated with the expression of p53, p16INK4a and bcl-2. RESULTS: Significant differences between NM and SSM were found for the nuclear area, OD, and perimeter (p<0.05). MI showed significant correlations with nuclear area, perimeter and Feret diameter (p<0.05). In relation to the Clark level, significant differences were found for OD (p<0.01) and circularity of nuclei (p<0.05) between levels II and IV, while the Breslow thickness was not significantly correlated with nuclear morphometric variables. Significantly negative correlations were observed between OD and the expression of p53 and bcl-2, while significant positive correlation was found between the nuclear circularity and p53 immunoreaction intensity. There was no significant correlation between the expression of p16INK4a protein and karyometric variables. CONCLUSION: OD and circularity are significantly correlated with p53 and bcl-2, and nuclear area with MI. These karyometric variables may determine a more aggressive phenotype of melanoma cells.

The once-daily human GLP-1 analogue liraglutide impacts appetite and energy intake in patients with type 2 diabetes after short-term treatment.

The aim was to investigate effects of liraglutide on appetite and energy intake in a randomized, placebo-controlled, double-blind, crossover study. Eighteen subjects with type 2 diabetes were assigned to treatment with once-daily subcutaneous liraglutide (increasing by weekly 0.6 mg increments) or placebo for 3 weeks. Appetite ratings were assessed using visual analogue scales during a 5-h meal test. Energy and macronutrient intake during the subsequent ad libitum lunch were also measured. After 3 weeks, mean postprandial and minimum hunger ratings were significantly lower with liraglutide 1.8 mg than placebo (p < 0.01), and the mean overall appetite score was significantly higher (p = 0.05), indicating reduced appetite. Liraglutide was associated with higher maximum fullness ratings (p = 0.001) and lower minimum ratings of prospective food consumption (p = 0.01). Mean estimated energy intake was 18% lower for liraglutide than placebo [estimated ratio 0.82 (95% CI 0.73;0.94); p = 0.004], but no significant differences in macronutrient distribution were noted. Findings suggest that reduced appetite and energy intake may contribute to liraglutide-induced weight loss.

Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue.

AIM: The effect on body composition of liraglutide, a once-daily human glucagon-like peptide-1 analogue, as monotherapy or added to metformin was examined in patients with type 2 diabetes (T2D). METHODS: These were randomized, double-blind, parallel-group trials of 26 [Liraglutide Effect and Action in Diabetes-2 (LEAD-2)] and 52 weeks (LEAD-3). Patients with T2D, aged 18-80 years, body mass index (BMI) < or =40 kg/m(2) (LEAD-2), < or =45 kg/m(2) (LEAD-3) and HbA1c 7.0-11.0% were included. Patients were randomized to liraglutide 1.8, 1.2 or 0.6 mg/day, placebo or glimepiride 4 mg/day, all combined with metformin 1.5-2 g/day in LEAD-2 and to liraglutide 1.8, 1.2 or glimepiride 8 mg/day in LEAD-3. LEAD-2/3: total lean body tissue, fat tissue and fat percentage were measured. LEAD-2: adipose tissue area and hepatic steatosis were assessed. RESULTS: LEAD-2: fat percentage with liraglutide 1.2 and 1.8 mg/metformin was significantly reduced vs. glimepiride/metformin (p < 0.05) but not vs. placebo. Visceral and subcutaneous adipose tissue areas were reduced from baseline in all liraglutide/metformin arms. Except with liraglutide 0.6 mg/metformin, reductions were significantly different vs. changes seen with glimepiride (p < 0.05) but not with placebo. Liver-to-spleen attenuation ratio increased with liraglutide 1.8 mg/metformin possibly indicating reduced hepatic steatosis. LEAD-3: reductions in fat mass and fat percentage with liraglutide monotherapy were significantly different vs. increases with glimepiride (p < 0.01). CONCLUSION: Liraglutide (monotherapy or added to metformin) significantly reduced fat mass and fat percentage vs. glimepiride in patients with T2D.

Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of the study was to compare the efficacy and safety of liraglutide in type 2 diabetes mellitus vs placebo and insulin glargine (A21Gly,B31Arg,B32Arg human insulin), all in combination with metformin and glimepiride. METHODS: This randomised (using a telephone or web-based randomisation system), parallel-group, controlled 26 week trial of 581 patients with type 2 diabetes mellitus on prior monotherapy (HbA(1c) 7.5-10%) and combination therapy (7.0-10%) was conducted in 107 centres in 17 countries. The primary endpoint was HbA(1c). Patients were randomised (2:1:2) to liraglutide 1.8 mg once daily (n = 232), liraglutide placebo (n = 115) and open-label insulin glargine (n = 234), all in combination with metformin (1 g twice daily) and glimepiride (4 mg once daily). Investigators, participants and study monitors were blinded to the treatment status of the liraglutide and placebo groups at all times. RESULTS: The number of patients analysed as intention to treat were: liraglutide n = 230, placebo n = 114, insulin glargine n = 232. Liraglutide reduced HbA(1c) significantly vs glargine (1.33% vs 1.09%; -0.24% difference, 95% CI 0.08, 0.39; p = 0.0015) and placebo (-1.09% difference, 95% CI 0.90, 1.28; p < 0.0001). There was greater weight loss with liraglutide vs placebo (treatment difference -1.39 kg, 95% CI 2.10, 0.69; p = 0.0001), and vs glargine (treatment difference -3.43 kg, 95% CI 4.00, 2.86; p < 0.0001). Liraglutide reduced systolic BP (-4.0 mmHg) vs glargine (+0.5 mmHg; -4.5 mmHg difference, 95% CI 6.8, -2.2; p = 0.0001) but not vs placebo (p = 0.0791). Rates of hypoglycaemic episodes (major, minor and symptoms only, respectively) were 0.06, 1.2 and 1.0 events/patient/year, respectively, in the liraglutide group (vs 0, 1.3, 1.8 and 0, 1.0, 0.5 with glargine and placebo, respectively). A slightly higher number of adverse events (including nausea at 14%) were reported with liraglutide, but only 9.8% of participants in the group receiving liraglutide developed anti-liraglutide antibodies. CONCLUSIONS/INTERPRETATION: Liraglutide added to metformin and sulfonylurea produced significant improvement in glycaemic control and bodyweight compared with placebo and insulin glargine. The difference vs insulin glargine in HbA(1c) was within the predefined non-inferiority margin. TRIAL REGISTRATION: ClinicalTrials.gov NCT00331851. FUNDING: The study was funded by Novo Nordisk A/S.