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

Understanding the Jus Cogens Debate : The Pervasive Influence of Legal Positivism and Legal Idealism

Although, today, jus cogens is a recognized element of international law and international legal discourse alike, many issues of vital importance to a well-functioning jus cogens regime remain unsettled. The current debate centres on the following six questions: (1) What is the source of jus cogens obligations? (2) What is the role of consent in the creation and modification of jus cogens norms? (3) How do we identify norms belonging to this category? (4) What does the category comprise? Are there such things, for example, as regional jus cogens or jus cogens principles? Are jus cogens rules necessarily rules of conduct? (5) What are the function and effects of the international jus cogens regime? (6) What is the function of jus cogens in international legal discourse? Overall, the intense scholarly debate had on peremptory international law over the last ten to twenty years has not been terribly productive. One important reason for this would seem to be the general failure of discussants to fully understand the relevance of some basic assumptions that they bring to bear on their respective analysis and consideration of the topic. To facilitate future constructive debate, this essay aims to clarify the relevance for any thoughtful consideration of jus cogens issues of legal positivism and legal idealism. While legal positivism and legal idealism are sets of theories offered to explain the concept of law, it is not surprising that lawyers of different camps will have different answers to questions (1) and (2). As argued in this essay, however, the influence of different theoretical approaches to the concept of law goes further than this - it permeates the entire jus cogens debate. Consequently, depending on whether lawyers take the position of a legal positivist or a legal idealist, they will be inclined to answer differently all questions (1)-(6)

The Applicability of GATT Article XX to China\u2019s WTO Accession Protocol in the Appellate Body Report of the China \u2013 Raw Materials Case: Suggestions for a Different Interpretative Approach

On 30 January 2012, the Appellate Body handed down a long awaited ruling in the dispute brought by the US, the EU and Mexico against several export restrictions imposed by China on raw materials. The three Appellate Members concluded inter alia that there is no basis in China\u2019s Accession Protocol to allow the application of GATT Article XX to Paragraph 11.3, the WTO-plus provision of the Accession Protocol requiring Beijing to eliminate export duties. While such AB interpretative result seriously runs the risk of creating a highly controversial and irrational aspect of the multilateral trade system, also difficult to reconcile with the principle of permanent sovereignty over natural resources, the present essay proposes a different coordinated reading between Paragraph 11.3 of the China\u2019s Accession Protocol and the GATT general exceptions\u2019 clause, with the aim of indicating a hermeneutic outcome in harmony with the principle of sustainable development enshrined in the Preamble of the WTO Agreement

Jus cogens in international investment law and arbitration

Despite growing reference to jus cogens in the jurisprudence of international courts and scholarly writings, the concept remains vague. What is jus cogens? Why does it matter? What are its effects? These questions remain unsettled, and the time is ripe for further in-depth investigation. This chapter aims at addressing this set of questions, focusing on the role of jus cogens in international investment law and arbitration. Jus cogens has played an important role in the evolution of international investment law, and illuminating the trajectory of this concept is important for the future of the field. In fact, not only can the study contribute to further clarifying the concept of jus cogens but it can also reinforce the perceived legitimacy of the international investment law system. These developments can be significant for international investment lawyers, international law scholars and other interested audiences