Background: Glucagon-like peptide 1 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. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

BackgroundWe examined the effect of the oral SIRT1 activator SRT2104 on cardiovascular function in otherwise healthy cigarette smokers.Methods and ResultsTwenty‐four otherwise healthy cigarette smokers participated in a randomized double‐blind, placebo‐controlled crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Plasma SRT2104 concentrations, serum lipid profile, plasma fibrinolytic factors, and markers of platelet and monocyte activation were measured at baseline and at the end of each treatment period together with an assessment of forearm blood flow during intra‐arterial bradykinin, acetylcholine, and sodium nitroprusside infusions. Three hours postdose, mean plasma SRT2104 concentration was 1328±748 ng/mL after 28 days of active treatment. Compared with placebo, serum lipid profile improved during SRT2104 administration, with reductions in serum total cholesterol (−11.6±20 versus 6±21 mg/dL), low‐density lipoprotein cholesterol (−10±17 versus 3±21 mg/dL), and triglyceride (−39.8±77 versus 13.3±57 mg/dL) concentrations (P<0.05 for all). All vasodilators produced a dose‐dependent increase in blood flow (P<0.0001) that was similar during each treatment period (P>0.05 for all). No significant differences in fibrinolytic or blood flow parameters were observed between placebo and SRT2014.ConclusionsSRT2104 appears to be safe and well tolerated and associated with an improved lipid profile without demonstrable differences in vascular or platelet function in otherwise healthy cigarette smokers.Clinical Trial Registrationhttp://www.clinicaltrials.gov. Unique identifier: NCT01031108.

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Sirukumab monotherapy showed greater improvements in DAS28 (ESR), but similar ACR50 response rates, versus adalimumab monotherapy.

P-selectin antagonism reduces thrombus formation in humans. J Thromb Haemost 2009; 7: 1915-9. Summary. Background: Interaction of P-selectin with its glycoprotein ligand (P-selectin glycoprotein ligand type 1) mediates inflammatory processes that may also include vascular thrombosis. Platelet P-selectin expression is increased in patients with coronary heart disease, and its antagonism represents a potential future therapeutic target for the prevention and treatment of atherothrombosis. Aim: To investigate the effects of the novel small molecule P-selectin antagonist PSI-697 on thrombus formation in humans. Methods and Results: In a double-blind randomized crossover study, thrombus formation was measured in 12 healthy volunteers, using the Badimon ex vivo perfusion chamber under conditions of low and high shear stress. Saline placebo, low-dose (2 M) and high-dose (20 M) PSI-697 and the glycoprotein IIb-IIIa receptor antagonist tirofiban (50 ng mL )1 ) were administered into the extracorporeal circuit prior to the perfusion chamber. As compared with saline placebo, blockade of platelet glycoprotein IIb-IIIa receptor with tirofiban produced 28% and 56% reductions in thrombus formation in the low-shear and high-shear chambers, respectively. PSI-697 caused a dose-dependent, but more modest, reduction in thrombus formation. Low-dose PSI-796 (2 M) reduced total thrombus area by 14% (P = 0.04) and 30% (P = 0.0002) in the low-shear and high-shear chambers, respectively. At the high dose (20 M), PSI-697 reduced total thrombus area by 18% (P = 0.0094) and 41% (P = 0.0008) in the low-shear and high-shear chambers, respectively. Conclusions: P-selectin antagonism with PSI-697 reduces ex vivo thrombus formation in humans. These findings provide further evidence that P-selectin antagonism may be a potential target for the prevention and treatment of cardiovascular disease.

Acute myeloid leukemia (AML) is driven by a minor fraction of leukemic stem cells (LSCs) whose persistence is considered being the primary cause of disease relapse. A detailed characterization of the surface immunophenotype of LSCs to discriminate them from bulk leukemic blasts may enable successful targeting of this population thereby improving patient outcomes in AML. To identify surface markers, which may reflect LSC activity at diagnosis, we performed a detailed analysis of 16 putative LSC markers in CD34/38 leukemic subcompartments of 150 diagnostic AML samples using multicolor flow cytometry. The most promising markers were then selected to determine a possible correlation of their expression with a recently published LSC gene signature. We found GPR56 and CLL‐1 to be the most prominently differently expressed surface markers in AML subcompartments. While GPR56 was highest expressed within the LSC‐enriched CD34+38− subcompartment as compared to CD34+38+ and CD34− leukemic bulk cells, CLL‐1 expression was lowest in CD34+38− leukemic cells and increased in CD34+38+ and CD34− blasts. Furthermore, high GPR56 surface expression in CD34+38− leukemic cells correlated with a recently published LSC gene expression signature and was associated with decreased overall survival in patients receiving intensive chemotherapy. In contrast, CLL‐1 expression correlated inversely with the LSC gene signature and was not informative on outcome. Our data strongly support GPR56 as a promising clinically relevant marker for identifying leukemic cells with LSC activity at diagnosis in CD34‐positive AML.

ObjectiveArterial stiffness increases with age, and is associated with adverse cardiovascular outcome including increased mortality. The effect of the oral small molecule SIRT1 activator, SRT2104, on arterial stiffness was examined in otherwise healthy cigarette smokers and participants with type 2 diabetes mellitus.Methods24 otherwise healthy cigarette smokers and 15 people with stable type 2 diabetes were randomised in a double-blind placebo-controlled crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Blood pressure was measured using non-invasive oscillatory sphygmomanometry. Pulse wave analysis and velocity were measured using applanation tonometry at baseline and the end of each treatment period. Owing to the small sample size and similar trends for both groups, data for the two groups were pooled (post hoc analysis).ResultsCompared to placebo, treatment with SRT2104 was associated with a significant reduction in augmentation pressure (p=0.0273) and a trend towards improvement in the augmentation index and corrected augmentation index (p>0.05 for both). However, no changes were observed in pulse wave velocity and time to wave reflection (p>0.05). Systolic and diastolic blood pressures remained unchanged throughout the study. Treatment by cohort interaction was not significant for any of the pulse wave parameters, suggesting that the response to SRT2104 in otherwise healthy smokers and people with diabetes was consistent.ConclusionsSRT2104 may improve measures of arterial stiffness in otherwise healthy cigarette smokers and in participants with type 2 diabetes. Definitive conclusions are not possible given the small sample size and exploratory nature of this analysis.Trial registration numberNCT01031108.

Despite achieving complete remission after intensive therapy, most patients with cytogenetically normal (CN) AML relapse due to the persistence of submicroscopic residual disease. In this pilot study, we hypothesized that detection of leukemia-specific mutations following consolidation treatment using a targeted parallel sequencing approach predicts relapse. We included 34 AML patients of whom diagnostic material and remission bone marrow slides after at least one cycle of consolidation were available. Isolated DNA was screened for mutations in 19 genes using an Ion Torrent sequencing platform. Furthermore, the variant allelic frequency of distinct mutations was validated by digital PCR and sequencing using a barcoding approach. Twenty-seven out of 34 patients could be analyzed for mutation clearance. We identified 68 somatic mutations at diagnosis (median, 3 mutations per patient; range 1-5) and 22 of these were still detected in 16 patients after consolidation therapy with a reliable sensitivity of 0.5% (median, 1 mutation; range 0-3). The most frequent noncleared mutations were found in DNMT3A. However, as persistence of these mutations has recently been shown to be without any impact on relapse risk, we performed survival and relapse risk analysis excluding DNMT3A mutations. Importantly, persistence of non-DNMT3A mutations was associated with a higher risk of AML relapse (7/8 pts versus 6/19 pts; P = .013) and with a shorter relapse-free survival (333 days vs. not reached; log-rank P = .0219). Detection of residual disease by routine targeted parallel sequencing proved feasible and effective as persistence of somatic mutations other than DNMT3A were prognostic for relapse in CN AML.