3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background: Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods: In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings: The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation: In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding: Novo Nordisk, Denmark

SEA-TRUTHING A SATELLITE TECHNIQUE FOR OCEAN SURFACE FLOW ESTIMATION

Program year: 1989/1990Digitized from print original stored in HDRFeature tracking is a technique that produces a sea surface velocity field from sequential images of sea surface brightness temperature derived from satellite measurements of upwelling radiation intensity. To test the validity of the vector fields produced by feature tracking, the trajectories of model water parcels moved by the vector field are compared with the trajectories of actual drifting buoys. Six buoys in the Gulf of Mexico during the spring of 1989 serve as the basis for the comparison. Using feature tracking on two different image pairs pairs I estimated two velocity vector fields. then developed and used a fourth-order Runge-Kutta integration routine to move model water parcels through the field, using derivatives supplied by bivariate interpolation directly from the velocity field. The correlation between parcel and buoy tracks is fairly good over the first 24 hours, although the results show wide variability and indicate a direction for improvement. Increased proficiency in feature tracking, advancement to time-dependent fields, and improved interpolation methods would allow vector fields derived by feature tracking to more closely mirror kilometer scale sea surface motion

Metabolism of Caffeine by Mouse Liver Microsomes: GSH or Cytosol Causes a Shift in Products From 1, 3, 7-Trimethylurate to a Substituted Diaminouracil

Incubation of [14C] caffeine with hepatic microsomes from male AKR/J mice resulted in the formation of several metabolites including 1, 3, 7-trimethylurate and 6-amino-5-(N-formylmethyl-amino)-1, 3-dimethyluracil. These two compounds comprised about 60% of products and are major urinary metabolites in several animals. When cytosol was included during incubation, there was a 14-fold increase in yield of the uracil at the expense of the urate; the combination of the two metabolites remained about 60% of total products. Cytosol alone was catalytically inert. Glutathione and other sulfhydryl compounds reproduced the effect of cytosol, and the action of cytosol was accounted for quantitatively by its sulfhydryl content. We propose that an oxidized intermediate of caffeine en route to trimethylurate is reduced by glutathione to the ring-opened uracil derivative