Background: Glucagon-like peptide 1 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. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

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The events which occur in the death of visceromotor neurons of the cervical region of the chick embryo's spinal cord have been analyzed by electron microscopy . These normal degenerative events are compared with those in the lumbosacral cord where nerve cell death was induced by removal of peripheral organs . The initial set of degenerative changes include a decrease in nuclear size, the clumping of chromatin beneath the nuclear envelope, an increase in electron opacity of the cells, the disappearance of Golgi bodies, and the disaggregation of polysomes . These events are followed by the loss of the nuclear envelope and most of the endoplasmic reticulum, the appearance of bundles of filaments, and the formation of many ribosome crystals . Ribosome crystals are seen only in the dying cells .Their abundance may indicate a drastic reduction in RNA synthesis as one of the initial events which lead to the death of these neurons . The neurons are finally subdivided and engulfed by cells of the normal glial population, and further breakdown of the cell fragments occurs in large phagocytic vesicles of the gliocytes .Death of cells plays a very prominent part in the embryonic development of vertebrate organisms (1-3) . It occurs during the differentiation and sculpturing of various organs, and in the elimination of structures that are useful only during a limited phase of the embryonic period . The mechanism of cell death in embryonic systems has not for the most part been identified . Many studies have indicated that it is under genetic control (4), but how this genetic control is mediated on a cellular level is completely unknown .During normal development, massive cell death occurs in the cervical motor column of the chick spinal cord between the 4th and 5th days of incubation (5) . As a result of this degenerative process, at least two-thirds of the cell population in this region is reduced to cellular debris and pycnotic cells within a 24 h period . Careful analysis of this area using the Cajal silver staining method revealed that the dying cells are preganglionic neurons and part of an abortive visceral system (5), a conclusion supported by experiments involving transplantation of the cervical cord to the thoracic region (6) . Previous work has indicated that the dying cells are removed by macrophages which invade the motor column and ingest the degenerating cells (5, 7) . After the 6th day of incubation, however, macrophages could not be identified ; therefore, it was presumed that they had migrated from the cord .In the chick embryo, massive cell death does not normally occur in any other regions of the spinal cord . However, most of the motor neurons in the lateral motor column of the lumbosacral cord will die after extirpation of the ipsilateral leg bud of a 2% day old embryo (8) . Nerve processes are not severed in the course of the extirpation, since leg nerves do not reach the base of the leg bud until the 4th day ; therefore, this cell death does not result from nerve cell damage . Light

A normal developmental pattern of the mitotic index, growth of villi and crypts, rate of cell extrusion, and number of villi per duodenal cross section is presented for mice ranging i n age from the seventeenth day of gestation through 48 days after birth. These patterns are correlated with the normal increases in both length and weight of the intestine as a whole during this period. Two periods were observed during which there is a 25% reduction i n the mitotic index. There is essentially n o change in the mitotic index after the twenty-first postnatal day. Approximately 43% of the 48-day villus-crypt height is reached by birth, and approximately 83% of the 48-day level is reached by the twenty-first day. No extrusion zones were observed in mice before birth, and a threefold increase in the rate of extrusion was observed between the fifteenth and twenty-first postnatal day. Growth of the villuscrypt epithelial cell population appears to be a result of a rate of cell extrusion which is much lower i n the young than in the adult animal.