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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Patients with diabetes play with a double-edged sword when it comes to deciding glucose and A1c target levels. On the one side, tight control has been shown to be crucial in avoiding long-term complications; on the other, tighter control leads to an increased risk of iatrogenic hypoglycemia, which is compounded when hypoglycemia unawareness sets in. Development of continuous glucose monitoring systems has led to the possibility of being able not only to detect hypoglycemic episodes, but to make predictions based on trends that would allow the patient to take preemptive action to entirely avoid the condition. Using an optimal estimation theory approach to hypoglycemia prediction, we demonstrate the effect of measurement sampling frequency, threshold level, and prediction horizon on the sensitivity and specificity of the predictions. We discuss how optimal estimators can be tuned to trade-off the false alarm rate with the rate of missed predicted hypoglycemic episodes. We also suggest the use of different alarm levels as a function of current and future estimates of glucose and the hypoglycemic threshold and prediction horizon.

Several low-Ni iron meteorites previously assigned to group IAB are reclassified IIICD on the basis of lower Ge, Ga, W and Ir concentrations and higher As concentrations; the low-Ni extreme of IIICD is now 62 mg/g, that of IAB is 64 mg/g. The resulting fractionation patterns in the two groups are quite similar. It has long been established that, in contrast to the magmatic iron meteorite groups, IAB and IIICD did not form by fractional crystallization of a metallic magma. Other models have been proposed, but all have serious flaws. A new model is proposed involving the formation of each iron in small pools of impact melt on a parent body consisting of material similar to the chondritic inclusions found in some IAB and IIICD irons, but initially unequilibrated. These impact melts ranged in temperatures from ~ 1190 K to ~ 1350 K. The degree of equilibration between melt and unmelted solids ranged from minimal at the lowest temperature to moderate at the highest temperature. The lowest temperature melts were near the cotectic in the Fe-Ni-S system with Ni contents of ~ 12 atom %. Upon cooling, these precipitated metal having ~ 600 mg/g Ni by equilibrium crystallization. The Ni-rich melt resulted from the melting of Ni-rich sulfides and metal in the unequilibrated chondritic parent. Low-Ni irons formed in high temperature melts near the composition of the FeS-Fe eutectic or somewhat more metal rich. We suggest that the decreasing Ge, Ga and refractory abundances with increasing Ni concentration reflect the trapping of these elements in oxide phases in the unequilibrated chondritic material, and that very little entered the Ni-rich melt parental to the Oktibbeha County iron. The remaining elements tended to have element/Ni ratios in the melts that were more or less independent of temperature. The remarkable correlation between I-Xe age of the chondritic inclusions and Ni content of the host metal is explained by a detailed evolution of (mega)regolith in which these groups originated. The most Ni-rich melts could only be generated from an unequilibrated chondrite parent; as the continuing deposition of impact energy produced increasingly higher grades of metamorphism, the maximum Ni content of the impact melts (and their subsequently precipitated metal) gradually decreased.