Novo Nordisk (Denmark)

BACKGROUND: The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. METHODS: In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. RESULTS: A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. CONCLUSIONS: In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.).

BACKGROUND: Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed. METHODS: In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions. RESULTS: The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]). CONCLUSIONS: In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

BACKGROUND: Cardiovascular disease (CVD) is a common comorbidity in type 2 diabetes (T2DM). CVD's prevalence has been growing over time. PURPOSE: To estimate the current prevalence of CVD among adults with T2DM by reviewing literature published within the last 10 years (2007-March 2017). METHODS: We searched Medline, Embase, and proceedings of major scientific meetings for original research documenting the prevalence of CVD in T2DM. CVD included stroke, myocardial infarction, angina pectoris, heart failure, ischemic heart disease, cardiovascular disease, coronary heart disease, atherosclerosis, and cardiovascular death. No restrictions were placed on country of origin or publication language. Two reviewers independently searched for articles and extracted data, adjudicating results through consensus. Data were summarized descriptively. Risk of bias was examined by applying the STROBE checklist. RESULTS: We analyzed data from 57 articles with 4,549,481 persons having T2DM. Europe produced the most articles (46%), followed by the Western Pacific/China (21%), and North America (13%). Overall in 4,549,481 persons with T2DM, 52.0% were male, 47.0% were obese, aged 63.6 ± 6.9 years old, with T2DM duration of 10.4 ± 3.7 years. CVD affected 32.2% overall (53 studies, N = 4,289,140); 29.1% had atherosclerosis (4 studies, N = 1153), 21.2% had coronary heart disease (42 articles, N = 3,833,200), 14.9% heart failure (14 studies, N = 601,154), 14.6% angina (4 studies, N = 354,743), 10.0% myocardial infarction (13 studies, N = 3,518,833) and 7.6% stroke (39 studies, N = 3,901,505). CVD was the cause of death in 9.9% of T2DM patients (representing 50.3% of all deaths). Risk of bias was low; 80 ± 12% of STROBE checklist items were adequately addressed. CONCLUSIONS: Globally, overall CVD affects approximately 32.2% of all persons with T2DM. CVD is a major cause of mortality among people with T2DM, accounting for approximately half of all deaths over the study period. Coronary artery disease and stroke were the major contributors.

We consider a mesoscopic region coupled to two leads under the influence of external timedependent voltages. The time dependence is coupled to source and drain contacts, the gates controlling the tunnel-barrier heights, or to the gates that define the mesoscopic region. We derive, with the Keldysh nonequilibrium-Green-function technique, a formal expression for the fully nonlinear, time-dependent current through the system. The analysis admits arbitary interactions in the mesoscopic region, but the leads are treated as noninteracting. For proportionate coupling to the leads, the time-averaged current is simply the integral between the chemical potentials of the time-averaged density of states, weighted by the coupling to the leads, in close analogy to the time-independent result of Meir and Wingreen [Phys. Rev. Lett. 68, 2512 (1992)]. Analytical and numerical results for the exactly solvable noninteracting resonant-tunneling system are presented. Due to the coherence between the leads and the resonant site, the current does not follow the driving signal adiabatically: a "ringing" current is found as a response to a voltage pulse, and a complex time dependence results in the case of harmonic driving voltages. We also establish a connection to recent linear-response calculations, and to earlier studies of electron-phonon scattering effects in resonant tunneling.

Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known. METHODS: We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients. RESULTS: In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P = 0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed. CONCLUSIONS: This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.).

Learning of continuous valued functions using neural network ensembles (committees) can give improved accuracy, reliable estimation of the generalization error, and active learning. The ambiguity is defined as the variation of the output of ensemble members averaged over unlabeled data, so it quantifies the disagreement among the networks. It is discussed how to use the ambiguity in combination with cross-validation to give a reliable estimate of the ensemble generalization error, and how this type of ensemble cross-validation can sometimes improve performance. It is shown how to estimate the optimal weights of the ensemble members using unlabeled data. By a generalization of query by committee, it is finally shown how the ambiguity can be used to select new training data to be labeled in an active learning scheme. 1 INTRODUCTION It is well known that a combination of many different predictors can improve predictions. In the neural networks community &amp;quot;ensembles&amp;quot; of neural networks h...

BACKGROUND: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive placebo. At baseline and at 13 weeks, all patients underwent an oral glucose-tolerance test, followed by an intravenous bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine. In addition, 35 patients underwent a hyperinsulinemic-euglycemic clamp study. The primary end point was a change in the level of glycated hemoglobin, and secondary end points were changes in beta-cell function, insulin sensitivity, and inflammatory markers. RESULTS: At 13 weeks, in the anakinra group, the glycated hemoglobin level was 0.46 percentage point lower than in the placebo group (P=0.03); C-peptide secretion was enhanced (P=0.05), and there were reductions in the ratio of proinsulin to insulin (P=0.005) and in levels of interleukin-6 (P<0.001) and C-reactive protein (P=0.002). Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and the body-mass index were similar in the two study groups. Symptomatic hypoglycemia was not observed, and there were no apparent drug-related serious adverse events. CONCLUSIONS: The blockade of interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation. (ClinicalTrials.gov number, NCT00303394 [ClinicalTrials.gov].).

BACKGROUND: The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity. SCOPE OF REVIEW: In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases. MAJOR CONCLUSIONS: Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders.

BACKGROUND: Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney failure, cardiovascular events, and death. Whether treatment with semaglutide would mitigate these risks is unknown. METHODS: ), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes. Prespecified confirmatory secondary outcomes were tested hierarchically. RESULTS: in the semaglutide group (P<0.001), the risk of major cardiovascular events 18% lower (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.029), and the risk of death from any cause 20% lower (hazard ratio, 0.80; 95% CI, 0.67 to 0.95, P = 0.01). Serious adverse events were reported in a lower percentage of participants in the semaglutide group than in the placebo group (49.6% vs. 53.8%). CONCLUSIONS: Semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes and chronic kidney disease. (Funded by Novo Nordisk; FLOW ClinicalTrials.gov number, NCT03819153.).

The authors review the Keldysh method of obtaining kinetic equations for normal and superconducting metals. The use of the method is illustrated by examples involving electron-impurity, electron-phonon, and electron-electron scattering, both within and beyond the quasiclassical approximation.

It has been observed in numerical simulations that a weight decay can improve generalization in a feed-forward neural network. This paper explains why. It is proven that a weight decay has two effects in a linear network. First, it suppresses any irrelevant components of the weight vector by choosing the smallest vector that solves the learning problem. Second, if the size is chosen right, a weight decay can suppress some of the effects of static noise on the targets, which improves generalization quite a lot. It is then shown how to extend these results to networks with hidden layers and non-linear units. Finally the theory is confirmed by some numerical simulations using the data from NetTalk.

BACKGROUND: Intracerebral hemorrhage is the least treatable form of stroke. We performed this phase 3 trial to confirm a previous study in which recombinant activated factor VII (rFVIIa) reduced growth of the hematoma and improved survival and functional outcomes. METHODS: We randomly assigned 841 patients with intracerebral hemorrhage to receive placebo (268 patients), 20 microg of rFVIIa per kilogram of body weight (276 patients), or 80 microg of rFVIIa per kilogram (297 patients) within 4 hours after the onset of stroke. The primary end point was poor outcome, defined as severe disability or death according to the modified Rankin scale 90 days after the stroke. RESULTS: Treatment with 80 microg of rFVIIa per kilogram resulted in a significant reduction in growth in volume of the hemorrhage. The mean estimated increase in volume of the intracerebral hemorrhage at 24 hours was 26% in the placebo group, as compared with 18% in the group receiving 20 microg of rFVIIa per kilogram (P=0.09) and 11% in the group receiving 80 microg (P<0.001). The growth in volume of intracerebral hemorrhage was reduced by 2.6 ml (95% confidence interval [CI], -0.3 to 5.5; P=0.08) in the group receiving 20 microg of rFVIIa per kilogram and by 3.8 ml (95% CI, 0.9 to 6.7; P=0.009) in the group receiving 80 microg, as compared with the placebo group. Despite this reduction in bleeding, there was no significant difference among the three groups in the proportion of patients with poor clinical outcome (24% in the placebo group, 26% in the group receiving 20 microg of rFVIIa per kilogram, and 29% in the group receiving 80 microg). The overall frequency of thromboembolic serious adverse events was similar in the three groups; however, arterial events were more frequent in the group receiving 80 microg of rFVIIa than in the placebo group (9% vs. 4%, P=0.04). CONCLUSIONS: Hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhage. (ClinicalTrials.gov number, NCT00127283 [ClinicalTrials.gov].).

Abstract Hepatocellular carcinoma (HCC) can have viral or non-viral causes 1–5 . Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need 6,7 . Here we report the progressive accumulation of exhausted, unconventionally activated CD8 + PD1 + T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8 + PD1 + T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8 + PD1 + CXCR6 + , TOX + , and TNF + T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8 + T cells or TNF neutralization, suggesting that CD8 + T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8 + PD1 + T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

Importance: The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown. Objective: To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly. Design, Setting, and Participants: Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes. Interventions: A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups. Main Outcomes and Measures: The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]). Results: Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%). Conclusions and Relevance: Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT03548987.

In the search for the molecular mechanism of insulin fibrillation, the kinetics of insulin fibril formation were studied under different conditions using the fluorescent dye thioflavin T (ThT). The effect of insulin concentration, agitation, pH, ionic strength, anions, seeding, and addition of 1-anilinonaphthalene-8-sulfonic acid (ANS), urea, TMAO, sucrose, and ThT on the kinetics of fibrillation was investigated. The kinetics of the fibrillation process could be described by the lag time for formation of stable nuclei (nucleation) and the apparent rate constant for the growth of fibrils (elongation). The addition of seeds eliminated the lag phase. An increase in insulin concentration resulted in shorter lag times and faster growth of fibrils. Shorter lag times and faster growth of fibrils were seen at acidic pH versus neutral pH, whereas an increase in ionic strength resulted in shorter lag times and slower growth of fibrils. There was no clear correlation between the rate of fibril elongation and ionic strength. Agitation during fibril formation attenuated the effects of insulin concentration and ionic strength on both lag times and fibril growth. The addition of ANS increased the lag time and decreased the apparent growth rate for insulin fibril formation. The ANS-induced inhibition appears to reflect the formation of amorphous aggregates. The denaturant, urea, decreased the lag time, whereas the stabilizers, trimethylamine N-oxide dihydrate (TMAO) and sucrose, increased the lag times. The results indicated that both nucleation and fibril growth were controlled by hydrophobic and electrostatic interactions. A kinetic model, involving the association of monomeric partially folded intermediates, whose concentration is stimulated by the air-water interface, leading to formation of the critical nucleus and thence fibrils, is proposed.

The medium-induced p⊥-broadening and induced gluon radiation spectrum of a high energy quark or gluon traversing a large nucleus is studied. Multiple scattering of the high energy parton in the nucleus is treated in the Glauber approximation. We show that −dE/dz, the radiative energy loss of the parton per unit length, grows as L, the length of the nuclear matter, as does the characteristic transverse momentum squared of the parton p2⊥w. We find −dE/dz = 18αsNcp2⊥w holds independent of the details of the parton-nucleon scatterings so long as L is large and so long as perturbative QCD applies at short distances. Numerical estimates suggest that p⊥-broadening and energy loss may be significantly enhanced in hot matter as compared to cold matter, thus making the study of such quantities a possible signal for quark-gluon plasma formation.

BACKGROUND: Intracerebral hemorrhage is the least treatable form of stroke and is associated with high mortality. Among patients who undergo computed tomography (CT) within three hours after the onset of intracerebral hemorrhage, one third have an increase in the volume of the hematoma related to subsequent bleeding. We sought to determine whether recombinant activated factor VII (rFVIIa) can reduce hematoma growth after intracerebral hemorrhage. METHODS: We randomly assigned 399 patients with intracerebral hemorrhage diagnosed by CT within three hours after onset to receive placebo (96 patients) or 40 microg of rFVIIa per kilogram of body weight (108 patients), 80 microg per kilogram (92 patients), or 160 microg per kilogram (103 patients) within one hour after the baseline scan. The primary outcome measure was the percent change in the volume of the intracerebral hemorrhage at 24 hours. Clinical outcomes were assessed at 90 days. RESULTS: Hematoma volume increased more in the placebo group than in the rFVIIa groups. The mean increase was 29 percent in the placebo group, as compared with 16 percent, 14 percent, and 11 percent in the groups given 40 microg, 80 microg, and 160 microg of rFVIIa per kilogram, respectively (P=0.01 for the comparison of the three rFVIIa groups with the placebo group). Growth in the volume of intracerebral hemorrhage was reduced by 3.3 ml, 4.5 ml, and 5.8 ml in the three treatment groups, as compared with that in the placebo group (P=0.01). Sixty-nine percent of placebo-treated patients died or were severely disabled (as defined by a modified Rankin Scale score of 4 to 6), as compared with 55 percent, 49 percent, and 54 percent of the patients who were given 40, 80, and 160 microg of rFVIIa, respectively (P=0.004 for the comparison of the three rFVIIa groups with the placebo group). Mortality at 90 days was 29 percent for patients who received placebo, as compared with 18 percent in the three rFVIIa groups combined (P=0.02). Serious thromboembolic adverse events, mainly myocardial or cerebral infarction, occurred in 7 percent of rFVIIa-treated patients, as compared with 2 percent of those given placebo (P=0.12). CONCLUSIONS: Treatment with rFVIIa within four hours after the onset of intracerebral hemorrhage limits the growth of the hematoma, reduces mortality, and improves functional outcomes at 90 days, despite a small increase in the frequency of thromboembolic adverse events.

IMPORTANCE: Weight loss of 5% to 10% can improve type 2 diabetes and related comorbidities. Few safe, effective weight-management drugs are currently available. OBJECTIVE: To investigate efficacy and safety of liraglutide vs placebo for weight management in adults with overweight or obesity and type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: Fifty-six-week randomized (2:1:1), double-blind, placebo-controlled, parallel-group trial with 12-week observational off-drug follow-up period. The study was conducted at 126 sites in 9 countries between June 2011 and January 2013. Of 1361 participants assessed for eligibility, 846 were randomized. Inclusion criteria were body mass index of 27.0 or greater, age 18 years or older, taking 0 to 3 oral hypoglycemic agents (metformin, thiazolidinedione, sulfonylurea) with stable body weight, and glycated hemoglobin level 7.0% to 10.0%. INTERVENTIONS: Once-daily, subcutaneous liraglutide (3.0 mg) (n = 423), liraglutide (1.8 mg) (n = 211), or placebo (n = 212), all as adjunct to 500 kcal/d dietary deficit and increased physical activity (≥150 min/wk). MAIN OUTCOMES AND MEASURES: Three coprimary end points: relative change in weight, proportion of participants losing 5% or more, or more than 10%, of baseline weight at week 56. RESULTS: Baseline weight was 105.7 kg with liraglutide (3.0-mg dose), 105.8 kg with liraglutide (1.8-mg dose), and 106.5 kg with placebo. Weight loss was 6.0% (6.4 kg) with liraglutide (3.0-mg dose), 4.7% (5.0 kg) with liraglutide (1.8-mg dose), and 2.0% (2.2 kg) with placebo (estimated difference for liraglutide [3.0 mg] vs placebo, -4.00% [95% CI, -5.10% to -2.90%]; liraglutide [1.8 mg] vs placebo, -2.71% [95% CI, -4.00% to -1.42%]; P < .001 for both). Weight loss of 5% or greater occurred in 54.3% with liraglutide (3.0 mg) and 40.4% with liraglutide (1.8 mg) vs 21.4% with placebo (estimated difference for liraglutide [3.0 mg] vs placebo, 32.9% [95% CI, 24.6% to 41.2%]; for liraglutide [1.8 mg] vs placebo, 19.0% [95% CI, 9.1% to 28.8%]; P < .001 for both). Weight loss greater than 10% occurred in 25.2% with liraglutide (3.0 mg) and 15.9% with liraglutide (1.8 mg) vs 6.7% with placebo (estimated difference for liraglutide [3.0 mg] vs placebo, 18.5% [95% CI, 12.7% to 24.4%], P < .001; for liraglutide [1.8 mg] vs placebo, 9.3% [95% CI, 2.7% to 15.8%], P = .006). More gastrointestinal disorders were reported with liraglutide (3.0 mg) vs liraglutide (1.8 mg) and placebo. No pancreatitis was reported. CONCLUSIONS AND RELEVANCE: Among overweight and obese participants with type 2 diabetes, use of subcutaneous liraglutide (3.0 mg) daily, compared with placebo, resulted in weight loss over 56 weeks. Further studies are needed to evaluate longer-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01272232.

OBJECTIVE: The efficacy and safety of adding liraglutide (a glucagon-like peptide-1 receptor agonist) to metformin were compared with addition of placebo or glimepiride to metformin in subjects previously treated with oral antidiabetes (OAD) therapy. RESEARCH DESIGN AND METHODS: In this 26-week, double-blind, double-dummy, placebo- and active-controlled, parallel-group trial, 1,091 subjects were randomly assigned (2:2:2:1:2) to once-daily liraglutide (either 0.6, 1.2, or 1.8 mg/day injected subcutaneously), to placebo, or to glimepiride (4 mg once daily). All treatments were in combination therapy with metformin (1g twice daily). Enrolled subjects (aged 25-79 years) had type 2 diabetes, A1C of 7-11% (previous OAD monotherapy for > or =3 months) or 7-10% (previous OAD combination therapy for > or =3 months), and BMI < or =40 kg/m(2). RESULTS: A1C values were significantly reduced in all liraglutide groups versus the placebo group (P < 0.0001) with mean decreases of 1.0% for 1.8 mg liraglutide, 1.2 mg liraglutide, and glimepiride and 0.7% for 0.6 mg liraglutide and an increase of 0.1% for placebo. Body weight decreased in all liraglutide groups (1.8-2.8 kg) compared with an increase in the glimepiride group (1.0 kg; P < 0.0001). The incidence of minor hypoglycemia with liraglutide ( approximately 3%) was comparable to that with placebo but less than that with glimepiride (17%; P < 0.001). Nausea was reported by 11-19% of the liraglutide-treated subjects versus 3-4% in the placebo and glimepiride groups. The incidence of nausea declined over time. CONCLUSIONS: In subjects with type 2 diabetes, once-daily liraglutide induced similar glycemic control, reduced body weight, and lowered the occurrence of hypoglycemia compared with glimepiride, when both had background therapy of metformin.