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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Although negative hepatic glucose production rates are physiologically impossible, they have been observed when hepatic glucose production is measured with the tracer-dilution technique during the hyperinsulinemic, euglycemic glucose clamp. Because hepatic glucose production is determined from the difference between tracer-derived glucose disposal and the known exogenous glucose infusion rate, the negative values for hepatic glucose production must result from an underestimation of glucose disposal by the tracer technique. In the current investigation, tracer-derived glucose disposal was measured in 25 subjects undergoing hyperinsulinemic, euglycemic clamps. Glucose disposal was measured with both radioactive and stable isotopes that utilize different methodologies, to determine whether discriminant metabolism of the isotopes versus methodological error leads to underestimation of tracer-derived glucose disposal. Both the radioactive and stable methodologies underestimated the exogenous glucose infusion rate during the hyperinsulinemic euglycemic clamp by 27 and 17%, respectively. Mean hepatic glucose production was -2.1 +/- 0.2 and -1.3 +/- 0.2 mg X kg-1 X min-1 as determined by the radioactive and stable isotope methodologies, respectively. Methodological error was an unlikely cause of this underestimation because it occurred with two different methodologies. The most likely explanation for underestimated rates of glucose disposal determined by the two types of isotope methodologies is discrepant metabolism of glucose tracers in comparison with unlabeled glucose.

This study addressed the controversial question of whether a negative-insulin-feedback loop exists in vivo. We utilized prehepatic insulin production, calculated by computerized deconvolution analysis of peripheral C-peptide concentration, as a measure of endogenous insulin secretion. Prehepatic insulin production was determined in 10 normal men who randomly underwent a control study and two additional studies involving different insulin infusion rates that achieved circulating insulin concentrations within the physiologic range during euglycemic clamps. The results demonstrate a dose-dependent suppression of prehepatic insulin production from 5.8 +/- 1.4 mU/min during the control study to 4.0 +/- 1.2 and 3.2 +/- 0.9 mU/min during plasma insulin levels of 34 +/- 4 and 61 +/- 6 microU/ml, respectively (P less than .05). Therefore, in contrast to recently reported results in vitro, insulin inhibits its own secretion in humans.

Addition of the DPP4 inhibitor PHX1149 to a stable regimen of metformin or metformin plus a glitazone in patients with type 2 diabetes was well tolerated and improved blood glucose control.