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Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist. Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1·8 mg once a day (n=233) or exenatide 10 μg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA 1c). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00518882. Mean baseline HbA 1c for the study population was 8·2%. Liraglutide reduced mean HbA 1c significantly more than did exenatide (−1·12% [SE 0·08] vs −0·79% [0·08]; estimated treatment difference −0·33; 95% CI −0·47 to −0·18; p<0·0001) and more patients achieved a HbA 1c value of less than 7% (54% vs 43%, respectively; odds ratio 2·02; 95% CI 1·31 to 3·11; p=0·0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (−1·61 mmol/L [SE 0·20] vs −0·60 mmol/L [0·20]; estimated treatment difference −1·01 mmol/L; 95% CI −1·37 to −0·65; p<0·0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide −3·24 kg vs exenatide −2·87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0·448, p<0·0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1·93 vs 2·60 events per patient per year; rate ratio 0·55; 95% CI 0·34 to 0·88; p=0·0131; 25·5% vs 33·6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode. Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations. Novo Nordisk A/S.

Background/Objectives: Exaggerated postprandial secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) may explain appetite reduction and weight loss after Roux-en-Y gastric bypass (RYGB), but causality has not been established. We hypothesized that food intake decreases after surgery through combined actions from GLP-1 and PYY. GLP-1 actions can be blocked using the GLP-1 receptor antagonist Exendin 9–39 (Ex-9), whereas PYY actions can be inhibited by the administration of a dipeptidyl peptidase-4 (DPP-4) inhibitor preventing the formation of PYY 3–36 . Subjects/Methods: Appetite-regulating gut hormones and appetite ratings during a standard mixed-meal test and effects on subsequent ad libitum food intake were evaluated in two studies: in study 1 , nine patients with type 2 diabetes were examined prospectively before and 3 months after RYGB with and without Ex-9. In study 2 , 12 RYGB-operated patients were examined in a randomized, placebo-controlled, crossover design on four experimental days with: (1) placebo, (2) Ex-9, (3) the DPP-4 inhibitor, sitagliptin, to reduce formation of PYY 3–36 and (4) Ex-9/sitagliptin combined. Results: In study 1, food intake decreased by 35% following RYGB compared with before surgery. Before surgery, GLP-1 receptor blockage increased food intake but no effect was seen postoperatively, whereas PYY secretion was markedly increased. In study 2 , combined GLP-1 receptor blockage and DPP-4 inhibitor mediated lowering of PYY 3–36 increased food intake by ~20% in RYGB patients, whereas neither GLP-1 receptor blockage nor DPP-4 inhibition alone affected food intake, perhaps because of concomitant marked increases in the unblocked hormone. Conclusions: Blockade of actions from only one of the two L-cell hormones, GLP-1 and PYY 3–36 , resulted in concomitant increased secretion of the other, probably explaining the absent effect on food intake on these experimental days. Combined blockade of GLP-1 and PYY actions increased food intake after RYGB, supporting that these hormones have a role in decreased food intake postoperatively.

Dulaglutide and liraglutide, both glucagon-like peptide-1 (GLP-1) receptor agonists, improve glycaemic control and reduce weight in patients with type 2 diabetes. In a head-to-head trial, we compared the safety and efficacy of once-weekly dulaglutide with that of once-daily liraglutide in metformin-treated patients with uncontrolled type 2 diabetes. We did a phase 3, randomised, open-label, parallel-group study at 62 sites in nine countries between June 20, 2012, and Nov 25, 2013. Patients with inadequately controlled type 2 diabetes receiving metformin (≥1500 mg/day), aged 18 years or older, with glycated haemoglobin (HbA1c) 7·0% or greater (≥53 mmol/mol) and 10·0% or lower (≤86 mmol/mol), and body-mass index 45 kg/m2 or lower were randomly assigned to receive once-weekly dulaglutide (1·5 mg) or once-daily liraglutide (1·8 mg). Randomisation was done according to a computer-generated random sequence with an interactive voice response system. Participants and investigators were not masked to treatment allocation. The primary outcome was non-inferiority (margin 0·4%) of dulaglutide compared with liraglutide for change in HbA1c (least-squares mean change from baseline) at 26 weeks. Safety data were collected for a further 4 weeks' follow-up. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01624259. We randomly assigned 599 patients to receive once-weekly dulaglutide (299 patients) or once-daily liraglutide (300 patients). 269 participants in each group completed treatment at week 26. Least-squares mean reduction in HbA1c was −1·42% (SE 0·05) in the dulaglutide group and −1·36% (0·05) in the liraglutide group. Mean treatment difference in HbA1c was −0·06% (95% CI −0·19 to 0·07, pnon-inferiority<0·0001) between the two groups. The most common gastrointestinal adverse events were nausea (61 [20%] in dulaglutide group vs 54 [18%] in liraglutide group), diarrhoea (36 [12%] vs 36 [12%]), dyspepsia (24 [8%] vs 18 [6%]), and vomiting (21 [7%] vs 25 [8%]), with similar rates of study or study drug discontinuation because of adverse events between the two groups (18 [6%] in each group). The hypoglycaemia rate was 0·34 (SE 1·44) and 0·52 (3·01) events per patient per year, respectively, and no severe hypoglycaemia was reported. Once-weekly dulaglutide is non-inferior to once-daily liraglutide for least-squares mean reduction in HbA1c, with a similar safety and tolerability profile. Eli Lilly and Company.

Patients with acute heart failure who received ularitide had greater reductions in systolic blood pressure and in levels of N-terminal pro–brain natriuretic peptide than those receiving placebo but had no improvement in cardiovascular mortality. Acute presentation with new-onset heart failure and rapid worsening of preexisting heart failure are two of the most common causes of hospitalization worldwide. 1 The disorder in each case is characterized by intravascular volume expansion and ventricular distention, which may cause myocardial injury in the absence of coronary artery disease or occlusion. 2 – 4 Episodes are associated with an accelerated rate of disease progression; each hospitalization for heart failure increases the risk of subsequent admissions as well as the risk of death from cardiovascular causes. 5 The first few hours after the initial presentation with acute heart failure may represent a period of . . .

Background Oral semaglutide is a tablet co-formulation of the human glucagon-like peptide-1 (GLP-1) analog semaglutide with the absorption enhancer sodium N -(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The absorption of coadministered oral drugs may be altered due to enhancement by SNAC, potential gastric emptying delay by semaglutide, or other mechanisms. Two one-sequence crossover trials investigated the effect of oral semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin. Methods In trial 1, 52 healthy subjects received lisinopril (20 mg single dose) or warfarin (25 mg single dose) with subsequent coadministration with SNAC alone (300 mg single dose), followed by oral semaglutide 20 mg once daily (steady state). In trial 2, 32 healthy subjects received digoxin (500 μg single dose) or metformin (850 mg twice daily for 4 days), with subsequent coadministration with SNAC alone followed by oral semaglutide, as in trial 1. Results There were no apparent effects of oral semaglutide on area under the plasma concentration–time curve (AUC) and maximum plasma concentration ( C max ) for lisinopril, warfarin, and digoxin. The AUC of metformin was increased by 32% (90% confidence interval 1.23–1.43) by oral semaglutide coadministration versus metformin alone, whereas the C max was unaffected. SNAC alone did not affect exposure of lisinopril, warfarin, digoxin, or metformin. Adverse events were in line with those previously observed for GLP-1 receptor agonists. Conclusions Oral semaglutide or SNAC alone did not appear to affect the exposure of lisinopril, warfarin, or digoxin, and, based on its wide therapeutic index, the higher metformin exposure with oral semaglutide was not considered clinically relevant.

Glucagon-like peptide-1 receptor agonists exenatide and liraglutide have been shown to improve glycaemic control and reduce bodyweight in patients with type 2 diabetes. We compared the efficacy and safety of exenatide once weekly with liraglutide once daily in patients with type 2 diabetes. We did a 26 week, open-label, randomised, parallel-group study at 105 sites in 19 countries between Jan 11, 2010, and Jan 17, 2011. Patients aged 18 years or older with type 2 diabetes treated with lifestyle modification and oral antihyperglycaemic drugs were randomly assigned (1:1), via a computer-generated randomisation sequence with a voice response system, to receive injections of once-daily liraglutide (1·8 mg) or once-weekly exenatide (2 mg). Participants and investigators were not masked to treatment assignment. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to week 26. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01029886. Of 912 randomised patients, 911 were included in the intention-to-treat analysis (450 liraglutide, 461 exenatide). The least-squares mean change in HbA1c was greater in patients in the liraglutide group (−1·48%, SE 0·05; n=386) than in those in the exenatide group (–1·28%, 0·05; 390) with the treatment difference (0·21%, 95% CI 0·08–0·33) not meeting predefined non-inferiority criteria (upper limit of CI <0·25%). The most common adverse events were nausea (93 [21%] in the liraglutide group vs 43 [9%] in the exenatide group), diarrhoea (59 [13%] vs 28 [6%]), and vomiting 48 [11%] vs 17 [4%]), which occurred less frequently in the exenatide group and with decreasing incidence over time in both groups. 24 (5%) patients allocated to liraglutide and 12 (3%) allocated to exenatide discontinued participation because of adverse events. Both once daily liraglutide and once weekly exenatide led to improvements in glycaemic control, with greater reductions noted with liraglutide. These findings, plus differences in injection frequency and tolerability, could inform therapeutic decisions for treatment of patients with type 2 diabetes. Eli Lilly and Company and Amylin Pharmaceuticals LLC.

Peptides from frogs are promising antibiotic candidates.Frog-derived synthetic peptides selectively targeted Gram-negative pathogens, sparing beneficial microbiota and human cells.Structure-guided modifications improved the antimicrobial potency by optimizing hydrophobicity and net charge.Lead peptides effectively reduced bacterial loads in murine models of Pseudomonas aeruginosa and Acinetobacter baumannii infections without toxicity. Novel antibiotics are urgently needed since bacteria are becoming increasingly resistant to existing antimicrobial drugs. Furthermore, available antibiotics are broad spectrum, often causing off-target effects on host cells and the beneficial microbiome. To overcome these limitations, we used structure-guided design to generate synthetic peptides derived from Andersonin-D1, an antimicrobial peptide (AMP) produced by the odorous frog Odorrana andersonii. We found that both hydrophobicity and net charge were critical for its bioactivity, enabling the design of novel, optimized synthetic peptides. These peptides selectively targeted Gram-negative pathogens in single cultures and complex microbial consortia, showed no off-target effects on human cells or beneficial gut microbes, and did not select for bacterial resistance. Notably, they also exhibited in vivo activity in two preclinical murine models. Overall, we present synthetic peptides that selectively target pathogenic infections and offer promising preclinical antibiotic candidates. [Display omitted] Synthetic peptides, inspired by the natural defenses of amphibians, demonstrate selective activity against Gram-negative pathogens while sparing the gut microbiota and Gram-positive strains. Rationally designed peptides showed remarkable potency, exhibiting no signs of resistance or toxicity. These results underscore the potential of peptide-based antibiotics to tackle multidrug-resistant bacterial infections. Peptides represent highly promising scaffolds for drug development, offering tunable properties and versatility regarding their targets. Synthetic peptides are at the forefront of innovation in combating antibiotic resistance due to their modular nature, which enables precise design optimization. Currently in the preclinical phase [Technology Readiness Level (TRL) 3 or 4], these peptide molecules have shown robust efficacy in both in vitro and animal models, underscoring their potential as next-generation therapeutics. Recent advancements in rational peptide design, enhanced by machine learning and structure-guided approaches, are significantly improving antimicrobial peptide (AMP) potency, stability, and selectivity. Narrow-spectrum AMPs, designed to target specific pathogens, not only reduce the risk of antimicrobial resistance, but also help preserve the microbiome. Furthermore, consortia-based experiments evaluating peptides in complex bacterial communities are refining their application against multidrug-resistant infections. With continuous investment and technological innovation, AMPs are on track to enter clinical trials within the next decade. Addressing scalability and regulatory challenges will be critical to unlocking their full potential as precision-based therapies, ultimately providing an adaptable and effective solution for tackling resistant infections.

OBJECTIVE: To evaluate efficacy and safety of switching from twice-daily exenatide to once-daily liraglutide or of 40 weeks of continuous liraglutide therapy. RESEARCH DESIGN AND METHODS: When added to oral antidiabetes drugs in a 26-week randomized trial (Liraglutide Effect and Action in Diabetes [LEAD]-6), liraglutide more effectively improved A1C, fasting plasma glucose, and the homeostasis model of β-cell function (HOMA-B) than exenatide, with less persistent nausea and hypoglycemia. In this 14-week extension of LEAD-6, patients switched from 10 μg twice-daily exenatide to 1.8 mg once-daily liraglutide or continued liraglutide. RESULTS: Switching from exenatide to liraglutide further and significantly reduced A1C (0.32%), fasting plasma glucose (0.9 mmol/l), body weight (0.9 kg), and systolic blood pressure (3.8 mmHg) with minimal minor hypoglycemia (1.30 episodes/patient-year) or nausea (3.2%). Among patients continuing liraglutide, further significant decreases in body weight (0.4 kg) and systolic blood pressure (2.2 mmHg) occurred with 0.74 episodes/patient-year of minor hypoglycemia and 1.5% experiencing nausea. CONCLUSIONS: Conversion from exenatide to liraglutide is well tolerated and provides additional glycemic control and cardiometabolic benefits.

Cell-penetrating peptides (CPPs) comprise a class of short polypeptides that possess the ability to selectively interact with the cytoplasmic membrane of certain cell types, translocate across plasma membranes and accumulate in the cell cytoplasm, organelles (e.g., the nucleus and mitochondria) and other subcellular compartments. CPPs are either of natural origin or de novo designed and synthesized from segments and patches of larger proteins or designed by algorithms. With such intrinsic properties, along with membrane permeation, translocation and cellular uptake properties, CPPs can intracellularly convey diverse substances and nanomaterials, such as hydrophilic organic compounds and drugs, macromolecules (nucleic acids and proteins), nanoparticles (nanocrystals and polyplexes), metals and radionuclides, which can be covalently attached via CPP N- and C-terminals or through preparation of CPP complexes. A cumulative number of studies on animal toxins, primarily isolated from the venom of arthropods and snakes, have revealed the cell-penetrating activities of venom peptides and toxins, which can be harnessed for application in biomedicine and pharmaceutical biotechnology. In this review, I aimed to collate examples of peptides from animal venoms and toxic secretions that possess the ability to penetrate diverse types of cells. These venom CPPs have been chemically or structurally modified to enhance cell selectivity, bioavailability and a range of target applications. Herein, examples are listed and discussed, including cysteine-stabilized and linear, α-helical peptides, with cationic and amphipathic character, from the venom of insects (e.g., melittin, anoplin, mastoparans), arachnids (latarcin, lycosin, chlorotoxin, maurocalcine/imperatoxin homologs and wasabi receptor toxin), fish (pardaxins), amphibian (bombesin) and snakes (crotamine and cathelicidins).

Purpose Myocardial dysfunction is common in sepsis but optimal treatment strategies are unclear. The inodilator, levosimendan was suggested as a possible therapy; however, the levosimendan to prevent acute organ dysfunction in Sepsis (LeoPARDS) trial found it to have no benefit in reducing organ dysfunction in septic shock. In this study we evaluated the effects of levosimendan in patients with and without biochemical cardiac dysfunction and examined its non-inotropic effects. Methods Two cardiac biomarkers, troponin I (cTnI) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and five inflammatory mediators were measured in plasma from patients recruited to the LeoPARDS trial at baseline and over the first 6 days. Mean total Sequential Organ Failure Assessment (SOFA) score and 28-day mortality were compared between patients with normal and raised cTnI and NT-proBNP values, and between patients above and below median values. Results Levosimendan produced no benefit in SOFA score or 28-day mortality in patients with cardiac dysfunction. There was a statistically significant treatment by subgroup interaction ( p  = 0.04) in patients with NT-proBNP above or below the median value. Those with NT-proBNP values above the median receiving levosimendan had higher SOFA scores than those receiving placebo (mean daily total SOFA score 7.64 (4.41) vs 6.09 (3.88), mean difference 1.55, 95% CI 0.43–2.68). Levosimendan had no effect on the rate of decline of inflammatory biomarkers. Conclusion Adding levosimendan to standard care in septic shock was not associated with less severe organ dysfunction nor lower mortality in patients with biochemical evidence of cardiac dysfunction.