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

Assessing legacy effects of a 12‐year irrigated cropping systems study with a post‐hoc bioassay

Abstract A healthy soil resource is vital to the continued success of irrigated agriculture in southern Alberta. A 12‐yr (2000–2011) irrigated cropping systems study was followed with a dry bean (Phaseolus vulgaris L.) field bioassay in 2012, to assess legacy effects of preceding management. Specifically, a comparison of conventional (CONV) and conservation (CONS) management (reduced tillage, cover crops, compost addition, narrow‐row dry bean) legacies was sought. However, rotational legacies such as preceding phase, length, preceding crop, and interval since previous dry bean were also assessed by the fully phased experimental setup. Only 1 of 18 possible soil management contrasts (CONV vs. CONS, 2000–2011) was significant for the dry bean bioassay in 2012, despite overwhelming evidence of improved soil health (microbial biomass C and β‐glucosidase activity) under CONS management. Monoculture wheat (Triticum aestivum L.) from 2000 to 2011 led to 2 d earlier maturity and higher disease incidence in bioassay dry bean. With wheat as a preceding crop, bioassay dry bean was significantly shorter (4 cm), earlier maturing (2 d), and lower yielding (by 21–35%) than with dry bean, potato (Solanum tuberosum L.), or sugar beet (Beta vulgaris L.) as preceding crops, largely due to volunteer wheat competition. Significantly enhanced bioassay yields (9–13%) with shorter intervals since previous dry bean demonstrated a “legume effect.” Overall, the dry bean bioassay was less effective at assessing soil management legacies (CONV vs. CONS) than rotational legacies such as preceding crop or interval since previous dry bean