14 research outputs found
Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.
Abstract
BACKGROUND:
The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.
METHODS:
We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy.
RESULTS:
In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups.
CONCLUSIONS:
Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)
An Analytical Model to Measure the Effectiveness of Safety Management Systems: Global Safety Improve Risk Assessment (G-SIRA) Method
Smart learning environments for a smart city: from the perspective of lifelong and lifewide learning
Pre-fusion structure of a human coronavirus spike protein
HKU1 is a human betacoronavirus that causes mild yet prevalent
respiratory disease1, and is related to the zoonotic SARS2 and
MERS3 betacoronaviruses, which have high fatality rates and
pandemic potential. Cell tropism and host range is determined
in part by the coronavirus spike (S) protein4, which binds cellular
receptors and mediates membrane fusion. As the largest known
class I fusion protein, its size and extensive glycosylation have
hindered structural studies of the full ectodomain, thus preventing
a molecular understanding of its function and limiting development
of effective interventions. Here we present the 4.0 Å resolution
structure of the trimeric HKU1 S protein determined using singleparticle
cryo-electron microscopy. In the pre-fusion conformation,
the receptor-binding subunits, S1, rest above the fusion-mediating
subunits, S2, preventing their conformational rearrangement.
Surprisingly, the S1 C-terminal domains are interdigitated and form
extensive quaternary interactions that occlude surfaces known in
other coronaviruses to bind protein receptors. These features, along
with the location of the two protease sites known to be important for
coronavirus entry, provide a structural basis to support a model of
membrane fusion mediated by progressive S protein destabilization
through receptor binding and proteolytic cleavage. These studies
should also serve as a foundation for the structure-based design of
betacoronavirus vaccine immunogens.NI