Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Study of the decoy receptors in helicobacter pylori gastritis

Objective: This study was designed to investigate the possible role of DcR3 and TL1A proteins in chronic Helicobacter pylori (HP) gastritis.Subjects and Methods: Thirty-six patients were included [26 patients with HP (+) and 10 patients with HP (-)] with symptoms of epigastric pain, digestive discomfort or melena. All patients underwent serum examination, as well as gastroscopy with biopsy. HP infection was diagnosed histologically. Triple HP eradication therapy took place, and the patients were reexamined by means of serum and endoscopic assessment and biopsy. Histological sections were evaluated for the degree of chronic inflammation, the inflammatory activity, the presence of intestinal metaplasia and atrophy, as well as the immunohistochemical expression of DcR3 protein in the gastric mucosa. The serum DcR3 and TL1A protein levels were assessed before and after HP eradication therapy.Results: After eradication therapy, the degree and the activity of mucosal inflammation of HP(+) patients were significantly lower (p = 0.001). No differences were observed between the two groups in regard to atrophy and intestinal metaplasia. The serum levels of the DcR3 and TL1A proteins of patients with HP (+) and HP (-) did not differ significantly (p = 0.244). By immunohistochemistry, there was increased mucosal expression of DcR3 in HP (+) patients, as compared to HP (-) controls (p = 0.008). Immunohistochemical detection of DcR3 decreased from marked to mild after eradication therapy (p = 0.019). There was a positive correlation between the immunohistochemical expression of DcR3 and the degree of inflammation, both before and after eradication therapy (p = 0.03 and p = 0.47, respectively). The immunohistochemical expression of DcR3 was not found to be correlated with inflammatory activity, atrophy or intestinal metaplasia (p> 0.05). Prior to eradication therapy, serum DcR3 levels were higher in the HP (+) patients with moderate or marked grade of mucosal immunostaining (p=0.037). Both the serum DcR3 and the immunopositivity in the biopsies decreased after eradication therapy in the majority of patients (p, NS). No statistically significant difference was identified between the immunohistochemical DcR3 detection and the serum TL1A (p=0.21) before and after eradication therapy.Conclusions: In chronic HP gastritis, there is increased expression of DcR3 in the gastric mucosa. This finding is not related to the presence of intestinal metaplasia or atrophy. Eradication of HP contributes to the reduction of inflammation and the decreased expression of DcR3 in the gastric mucosa. There was no correlation between the serum levels of DcR3 and the presence of HP, the activity of inflammation, atrophy or intestinal metaplasia. Moreover, there was no correlation between TL1A and histological parameters (inflammation, atrophy, intestinal metaplasia), the serum levels of DcR3 or the degree of DcR3 immunohistochemical expression in biopsy material. In patients with chronic gastritis, DcR3 protein could potentially be used as biomarker for inflammation. Towards this direction, a prospective study will be needed.Σκοπός: Η μελέτη αυτή σχεδιάστηκε με σκοπό να διερευνηθεί ο πιθανός ρόλος των πρωτεϊνών DcR3 και TL1A στη χρόνια γαστρίτιδα από ελικοβακτηρίδιο του πυλωρού (ΕΠ).Ασθενείς και Μέθοδοι: Συμπεριλήφθηκαν 36 ασθενείς [26 ασθενείς με ΕΠ(+) και 10 ασθενείς με ΕΠ(-)] με συμπτώματα επιγαστρικού άλγους, δυσπεπτικά ενοχλήματα ή και μέλαινες κενώσεις. Οι ασθενείς υποβλήθηκαν σε λήψη ορού αίματος, ενδοσκοπικό έλεγχο και λήψη βιοψιών, με τις οποίες αποδείχθηκε η παρουσία ΕΠ στο γαστρικό βλεννογόνο. Ακολούθησε θεραπεία εκρίζωσης με τριπλή φαρμακευτική αγωγή και οι ασθενείς υποβλήθηκαν εκ νέου σε λήψη ορού αίματος, ενδοσκοπικό έλεγχο και λήψη βιοψιών. Κατά την ιστολογική εξέταση εκτιμήθηκε ο βαθμός χρόνιας φλεγμονής, η ενεργός δραστηριότητα της φλεγμονής, η παρουσία εντερικής μεταπλασίας και ατροφίας, καθώς και η ανοσοϊστοχημική έκφραση της πρωτεΐνης DcR3 στο γαστρικό βλεννογόνο. Τα επίπεδα των πρωτεϊνών DcR3 και TL1Α στον ορό των ασθενών εκτιμήθηκαν πριν και μετά την θεραπεία εκρίζωσης του ΕΠ.Αποτελέσματα: Στους ασθενείς με ΕΠ(+), μετά την αγωγή εκρίζωσης ο βαθμός της φλεγμονής και η ενεργός δραστηριότητά της μειώθηκαν στατιστικώς σημαντικά (p=0,001). Δεν παρατηρήθηκαν διαφορές στις δυο ομάδες όσον αφορά την ατροφία και την εντερική μεταπλασία. Τα επίπεδα των πρωτεϊνών DcR3 και TL1A στον ορό των ασθενών με ΕΠ(+) και ΕΠ(-) δεν βρέθηκε να διαφέρουν στατιστικώς (p=0,244). Με τη μέθοδο της ανοσοϊστοχημείας, το DcR3 στο γαστρικό βλεννογόνο εκφράζονταν περισσότερο στους ασθενείς με ΕΠ(+), σε σύγκριση με τους μάρτυρες ΕΠ (-) (p=0,008). Στους ασθενείς μετά από την αγωγή εκρίζωσης η ανοσοϊστοχημική ανίχνευση του DcR3 μειώθηκε από έντονου σε ήπιου βαθμού (p=0,019). Διαπιστώθηκε συσχέτιση της ανοσοϊστοχημικής έκφρασης του DcR3 με το βαθμό φλεγμονής, τόσο πριν, όσο και μετά την αγωγή εκρίζωσης (p=0,03 και p=0,47, αντιστοίχως). Η ανοσοϊστοχημική έκφραση του DcR3 δεν βρέθηκε να σχετίζεται στατιστικώς με την ενεργό δραστηριότητα, την ατροφία ή την εντερική μεταπλασία (p>0,05). Στους ασθενείς με ΕΠ(+) πριν την αγωγή εκρίζωσης, τo DcR3 του ορού ήταν υψηλότερο σε εκείνους που είχαν έντονου ή μέτριου βαθμού ανοσοϊστοχημική χρώση στις βιοψίες στομάχου (p=0,037). Μετά τη θεραπεία εκρίζωσης, τόσο το DcR3 του ορού, όσο και η ανοσοθετικότητα στις βιοψίες ελαττώθηκαν στην πλειοψηφία των ασθενών (p, NS). Δεν βρέθηκε στατιστικά σημαντική διαφορά ανάμεσα στην ανοσοϊστοχημική ανίχνευση του DcR3 και του TL1A ορού (p=0,21) πριν και μετά την αγωγή εκρίζωσης.Συμπεράσματα: Στη χρόνια γαστρίτιδα από ΕΠ παρατηρείται αυξημένη έκφραση του DcR3 στο βλεννογόνο του στομάχου. Η αυξημένη αυτή έκφραση δεν σχετίζεται με την παρουσία εντερικής μεταπλασίας ή ατροφίας. Η εκρίζωση του ΕΠ συμβάλλει στη μείωση της φλεγμονής και στη μειωμένη έκφραση του DcR3 στο γαστρικό βλεννογόνο. Δεν διαπιστώθηκε συσχέτιση μεταξύ των επιπέδων του DcR3 του ορού και της παρουσίας ΕΠ, της ενεργού δραστηριότητας της φλεγμονής, της ατροφίας ή της εντερικής μεταπλασίας. Επιπλέον, δεν ανευρέθη συσχέτιση του TL1Α με τις ιστολογικές παραμέτρους (φλεγμονή, ατροφία, εντερική μεταπλασία), με τα επίπεδα του DcR3 στον ορό ή με την ανοσοϊστοχημική έκφρασή του σε υλικό βιοψίας. Στον πληθυσμό των ασθενών με χρόνια γαστρίτιδα, η πρωτεΐνη DcR3 θα μπορούσε δυνητικά να αποτελέσει δείκτη παρακολούθησης της φλεγμονής. Προς την κατεύθυνση αυτή θα απαιτηθεί προοπτική μελέτη

Streptococcus thoraltensis Bacteremia: First Described Case as a Fever of Unknown Origin in Human

Streptococcus thoraltensis has mainly been reported to cause infections in animals. Its clinical significance as a human pathogen has not yet been fully elucidated and needs further investigation. We describe here a case of bacteremia attributed to S. thoraltensis in a 55-year-old female patient admitted to our department due to fever of unknown origin. To the best of our knowledge, this is the first reported case of S. thoraltensis bacteremia in a human and the first reported case of S. thoraltensis as a cause of fever of unknown origin in human

Lessons From a Diabetes Clinic: Achieving Glycemic Goals and Clinical Use of Antidiabetic Agents in Patients With Type 2 Diabetes

The proportion of patients with type 2 diabetes who achieve their glycemic goals remains low. We examined medical records and A1C results from patient visits to our referral diabetes center between 21 March to 20 July 2018. After stratifying patients into four groups—monotherapy, dual therapy, triple therapy, or insulin therapy—we found that the target A1C of ≤7.0% was achieved by 86% of patients and that A1C was uniformly low across the treatment categories. Our individualized approach, which included high use of glucagon-like peptide-1 receptor agonists and low use of sulfonylureas, may have contributed to these results.</jats:p

934-P: Association between CTRB1/2 RS7202877 (T&amp;gt;G) Polymorphism and Glycemic Response to Liraglutide in Greek People with Type 2 Diabetes

Previous research has demonstrated an association between genetic variation in the CTRB1/2 gene and response to incretin therapies. We aimed to evaluate the role of CTRB1/2 rs7202877 (T&amp;gt;G) polymorphism in glycemic response to liraglutide among Greek people with T2D. 116 adults with T2D (51% female, mean BMI 35.4±6.4 kg/m2, mean age 68.3±10.9 years), who had been on treatment with liraglutide for at least 6 months were genotyped for the rs7202877 polymorphism, using real-time PCR. Responders met at least one of the following criteria: i) achievement of good glycemic control defined as HbA1c level of &amp;lt;7%, either at 3 or 6 months after treatment initiation, ii) reduction of the baseline HbA1c levels by ≥1% after 3 or 6 months of liraglutide use, and iii) maintenance of the optimal glucose control (HbA1c &amp;lt;7%) that a patient had before switching to liraglutide, after 3 or 6 months of treatment. Patients who failed to fulfil any of those criteria, were characterized as non-responders. 81 (70%) patients were classified as responders and 35 (30%) as non-responders. 97 (84%) patients were homozygous for the wild type T allele (TT) and 19 (16%) patients carried one polymorphic G allele (TG). Heterozygotes tended to have better response to liraglutide treatment; still, the difference was not significant (OR: 1.25, 95% CI: 0.4, 3.8, P=0.69). The probability of being a responder was 45% greater, when the baseline HbA1c was increased by 1% (adjusted for gender and baseline weight OR: 1.45, 95% CI: 1.05, 2.1, P=0.048). Additionally, an increase in baseline weight by 10 kg was associated with 26% reduced probability of being a responder (adjusted for gender and baseline HbA1c OR: 0.97, 95% CI: 0.94, 0.99, P=0.011). Our findings do not suggest a role of CTRB1/2 rs7202877 in affecting glycemic response to liraglutide. Lower baseline body weight and higher baseline glycemia might be related to better glycemic control following treatment with liraglutide. Disclosure A. Kyriakidou: None. A.V. Kyriazou: Research Support; Self; Novo Nordisk A/S. T. Koufakis: None. Y. Vasilopoulos: None. I. Avramidis: None. S. Baltagiannis: None. E. Manthou: None. D.G. Goulis: None. P. Zebekakis: None. K. Kotsa: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; Menarini Group. Other Relationship; Self; Novo Nordisk Inc. Funding Novo Nordisk (91220) </jats:sec

935-P: Effect of CTRB1/2 RS7202877 (T&amp;gt;G) Polymorphism on Weight Loss Response to Liraglutide Treatment in Greek People with Type 2 Diabetes

Previous studies have demonstrated an association between gene polymorphisms and weight loss response to GLP-1 RA therapy. We aimed to evaluate the role of rs7202877 (T&amp;gt;G) polymorphism in CTRB1/2 gene in weight loss response to liraglutide among Greek people with T2D. 116 adults with T2D (51% female, mean BMI 35.4±6.4 kg/m2, mean age 68.3±10.9 years), who had been on treatment with liraglutide for at least 6 months were genotyped for the rs7202877 polymorphism, using real-time PCR. Responders were defined as subjects who lost 3% or more of their baseline weight, whereas non-responders those who lost less than 3% of their initial weight after 3 or 6 months of liraglutide administration. 77 (66%) individuals were classified as responders and 39 (34%) as non-responders. 97 (84%) patients were homozygous for the wild type rs7202877 T allele (TT) and 19 (16%) patients carried one polymorphic G allele (TG). The probability of being weight loss responder was increased by 12%, when carrying the G allele; however, the result did not achieve significance (OR:1.12, 95% 0.4, 3.2, P=0.84). In the response group, weight was reduced by 5.9 kg (95% CI: -6.9, -4.9, P&amp;lt;0.0001) and by 6.4 kg (95% CI: -8, -4.9, P&amp;lt;0.0001) from baseline to 3 and 6 months, respectively. More non-responders were treated with a combination of oral agents and insulin at baseline, compared to responders (OR: 0.25, 95% CI: 0.07, 0.84, P=0.008). Both responders and non-responders exhibited a reduction in HbA1c during the study (-0.9%, P&amp;lt;0.0001 and -0.5%, P=0.008, respectively). The probability of being a weight loss responder was decreased by 26% for every 10 kg increase in baseline weight (adjusted for baseline HbA1c OR: 0.97, 95% CI: 0.95, 0.99, P=0.027). Our findings do not suggest a role of CTRB1/2rs7202877 polymorphism in affecting weight loss response to liraglutide in Greek people with T2D. In contrast, lower baseline body weight might be related to better weight control following treatment with liraglutide. Disclosure A.V. Kyriazou: Research Support; Self; Novo Nordisk A/S. A. Kyriakidou: None. T. Koufakis: None. Y. Vasilopoulos: None. I. Avramidis: None. S. Baltagiannis: None. E. Manthou: None. D.G. Goulis: None. P. Zebekakis: None. K. Kotsa: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; Menarini Group. Other Relationship; Self; Novo Nordisk Inc. Funding Novo Nordisk (91220) </jats:sec