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

Towards applying computational complexity to foundations of physics

In one of his early papers, D. Grigoriev analyzed the decidability and computational complexity of different physical theories. This analysis was motivated by the hope that this analysis would help physicists. In this paper, we survey several similar ideas that may be of help to physicists. We hope that further research may lead to useful physical applications.

Towards Applying Computational Complexity to Foundations of

In one of his early papers, D. Grigoriev analyzed the decidability and computational complexity of different physical theories. This analysis was motivated by the hope that this analysis would help physicists. In this paper, we survey several similar ideas that may be of help to physicists. We hope that further research may lead to useful physical applications.

To Properly Reflect Physicists\u27 Reasoning about Randomness, We Also Need a Maxitive (Possibility) Measure

According to the traditional probability theory, events with a positive but very small probability can occur (although very rarely). For example, from the purely mathematical viewpoint, it is possible that the thermal motion of all the molecules in a coffee cup goes in the same direction, so this cup will start lifting up. In contrast, physicists believe that events with extremely small probability cannot occur. In this paper, we show that to get a consistent formalization of this belief, we need, in addition to the original probability measure, to also consider a maxitive (possibility) measure

To Properly Reflect Physicists’ Reasoning about Randomness, We Also Need a Maxitive (Possibility

According to the traditional probability theory, events with a positive but very small probability can occur (although very rarely). For example, from the purely mathematical viewpoint, it is possible that the thermal motion of all the molecules in a coffee cup goes in the same direction, so this cup will start lifting up. In contrast, physicists believe that events with extremely small probability cannot occur. In this paper, we show that to get a consistent formalization of this belief, we need, in addition to the original probability measure, to also consider a maxitive (possibility) measure. We also show that the resulting advanced and somewhat difficult-to-described definition can be actually viewed as a particular case of something very natural: the general notion of boundedness. c ○ 2007 World Academic Press, UK. All rights reserved.