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

Evaluation of Mercury Contamination in Fungi Boletus Species from Latosols, Lateritic Red Earths, and Red and Yellow Earths in the Circum-Pacific Mercuriferous Belt of Southwestern China.

For the first time, highly elevated levels of mercury (Hg) have been documented for several species of the edible Fungi genus Boletus growing in latosols, lateritic red earths, and red and yellow earths from the Yunnan province of China. Analysis of Hg concentrations in the genus suggests that geogenic Hg is the dominant source of Hg in the fungi, whereas anthropogenic sources accumulate largely in the organic layer of the forest soil horizon. Among the 21 species studied from 32 locations across Yunnan and 2 places in Sichuan Province, the Hg was found at elevated level in all samples from Yunnan but not in the samples from Sichuan, which is located outside the mercuriferous belt. Particularly abundant in Hg were the caps of fruiting bodies of Boletus aereus (up to 13 mg kg-1 dry matter), Boletus bicolor (up to 5.5 mg kg-1 dry matter), Boletus edulis (up to 22 mg kg-1 dry matter), Boletus luridus (up to 11 mg kg-1 dry matter), Boletus magnificus (up to 13 mg kg-1 dry matter), Boletus obscureumbrinus (up to 9.4 mg kg-1 dry matter), Boletus purpureus (up to 16 mg kg-1 dry matter), Boletus sinicus (up to 6.8 mg kg-1 dry matter), Boletus speciosus (up to 4.9mg kg-1 dry matter), Boletus tomentipes (up to 13 mg kg-1 dry matter), and Boletus umbriniporus (up to 4.9 mg kg-1 dry matter). Soil samples of the 0-10 cm topsoil layer from the widely distributed locations had mercury levels ranging between 0.034 to 3.4 mg kg-1 dry matter. In Yunnan, both the soil parent rock and fruiting bodies of Boletus spp. were enriched in Hg, whereas the same species from Sichuan, located outside the mercuriferous belt, had low Hg concentrations, suggesting that the Hg in the Yunnan samples is mainly from geogenic sources rather than anthropogenic sources. However, the contribution of anthropogenically-derived Hg sequestered within soils of Yunnan has not been quantified, so more future research is required. Our results suggest that high rates of consumption of Boletus spp. from Yunnan can deliver relatively high doses of Hg to consumers, but that rates can differ widely because of large variability in mercury concentrations between species and locations

Summary of results of Hg determination in fungal certified reference materials (mg kg^-1 dry matter).

<p>Summary of results of Hg determination in fungal certified reference materials (mg kg^-1 dry matter).</p

Relationships between Hg concentration in the caps (y = 2.2142 + 6.4298 * x; r = 0.9229; p < 0.0001; r² = 0.8517) and stipes (y = 0.9553 + 2.7493 * x; r = 0.8907; p < 0.0001; r² = 0.7933) of the fruiting bodies of <i>B</i>. <i>edulis</i> from the Yunnan Province and soil beneath the fruiting bodies.

<p>Relationships between Hg concentration in the caps (y = 2.2142 + 6.4298 * x; r = 0.9229; p < 0.0001; r² = 0.8517) and stipes (y = 0.9553 + 2.7493 * x; r = 0.8907; p < 0.0001; r² = 0.7933) of the fruiting bodies of <i>B</i>. <i>edulis</i> from the Yunnan Province and soil beneath the fruiting bodies.</p

Mercury concentration in mushrooms of genus <i>Boletus</i> and soil substratum from the China and Poland, quotient of Hg concentration in caps to stipes (Q_C/S), and quotient of Hg concentration in cap/stipe to soil beneath the fruiting bodies (BCF; bioconcentration factor).

<p>Notes:</p><p>*(see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0143608#pone.0143608.g001" target="_blank">Fig 1</a>);</p><p>**(number of individuals);</p><p>WD (without data)</p><p>Mercury concentration in mushrooms of genus <i>Boletus</i> and soil substratum from the China and Poland, quotient of Hg concentration in caps to stipes (Q_C/S), and quotient of Hg concentration in cap/stipe to soil beneath the fruiting bodies (BCF; bioconcentration factor).</p

Relationships between Hg concentration in the caps (y = 1.4106 + 5.7865 * x; r = 0.7769 p < 0.0001; r² = 0.6036) and stipes (y = 0.8913 + 2.4557 * x; r = 0.7312; p > 0.0001; r² = 0.5346) of the fruiting bodies of <i>Boletus</i> spp. from the Yunnan and Sichuan Provinces and soil beneath the fruiting bodies.

<p>Relationships between Hg concentration in the caps (y = 1.4106 + 5.7865 * x; r = 0.7769 p < 0.0001; r² = 0.6036) and stipes (y = 0.8913 + 2.4557 * x; r = 0.7312; p > 0.0001; r² = 0.5346) of the fruiting bodies of <i>Boletus</i> spp. from the Yunnan and Sichuan Provinces and soil beneath the fruiting bodies.</p