Journal of Diabetes Investigation, Год журнала: 2024, Номер 15(9), С. 1177 - 1190
Опубликована: Июнь 14, 2024
Imeglimin is a recently approved oral antidiabetic agent that improves insulin resistance, and promotes secretion from pancreatic β-cells. Here, we investigated the effects of imeglimin on glucagon α-cells.
Язык: Английский
New England Journal of Medicine, Год журнала: 2024, Номер 391(4), С. 311 - 319
Опубликована: Июнь 7, 2024
BackgroundDual agonism of glucagon receptor and glucagon-like peptide-1 (GLP-1) may be more effective than GLP-1 alone for treating metabolic dysfunction–associated steatohepatitis (MASH). The efficacy safety survodutide (a dual agonist receptor) in persons with MASH liver fibrosis are unclear.MethodsIn this 48-week, phase 2 trial, we randomly assigned adults biopsy-confirmed stage F1 through F3 a 1:1:1:1 ratio to receive once-weekly subcutaneous injections at dose 2.4, 4.8, or 6.0 mg placebo. trial had two phases: 24-week rapid-dose-escalation phase, followed by maintenance phase. primary end point was histologic improvement (reduction) no worsening fibrosis. Secondary points included decrease fat content least 30% biopsy-assessed one stage.ResultsA total 293 participants received Improvement occurred 47% the 2.4-mg group, 62% those 4.8-mg 43% 6.0-mg as compared 14% placebo group (P<0.001 quadratic dose–response curve best-fitting model). A 63% 67% 57% group; 34%, 36%, 22%, respectively. Adverse events that were frequent nausea (66% vs. 23%), diarrhea (49% vomiting (41% 4%); serious adverse 8% 7% placebo.ConclusionsSurvodutide superior respect without fibrosis, warranting further investigation 3 trials. (Funded Boehringer Ingelheim; 1404-0043 ClinicalTrials.gov number, NCT04771273; EudraCT 2020-002723-11.)
Язык: Английский
Процитировано
146
Journal of Hepatology, Год журнала: 2023, Номер 79(6), С. 1557 - 1565
Опубликована: Авг. 9, 2023
The principle pathological drivers of metabolic dysfunction associated steatohepatitis (MASH) are obesity and insulin resistance, rendering them key therapeutic targets. As Glucagon-like Peptide 1 receptor agonists (GLP-1RA) have been licensed for the treatment diabetes they were one first such drugs to be evaluated in patients with MASH. Successful phase 2a 2b studies resulted progression Phase 3 clinical trials. Alongside GLP-1RA, newer combinations Glucagon agonism and/or Glucose-dependent Insulinotropic (GIP) explored related patient groups evidence improvements weight loss, resistance non-invasive liver parameters. There remains debate as whether GLP-1 direct, independent effects improve MASH or impact on pathophysiology through weight, glycaemic control. Combinations being although this needs weighed against cumulative side-effect burden, potential drug-drug interactions cost goods. is also uncertainty regarding optimal ratio glucagon GIP combination agents, antagonism indeed approach. Finally, there multiple hypothetical permutations combining gut hormone emerging assets field. Given that likely dominant mode action upstream initial might focus agents which shown a more direct effect fibrosis would include FGF21 pan-PPAR
Язык: Английский
Процитировано
85
The Lancet Diabetes & Endocrinology, Год журнала: 2024, Номер 12(3), С. 162 - 173
Опубликована: Фев. 5, 2024
Язык: Английский
Процитировано
81
Peptides, Год журнала: 2023, Номер 161, С. 170939 - 170939
Опубликована: Янв. 3, 2023
Long-acting analogues of the naturally occurring incretin, glucagon-like peptide-1 (GLP-1) and those modified to interact also with receptors for glucose-dependent insulinotropic polypeptide (GIP) have shown high glucose-lowering weight-lowering efficacy when administered by once-weekly subcutaneous injection. These herald an exciting new era in peptide-based therapy type 2 diabetes (T2D) obesity. Of note is GLP-1R agonist semaglutide, available oral injectable formulations clinical trials combined long-acting amylin analogue, cagrilintide. Particularly both glucose- weight lowering capacities has been observed GLP-1R/GIP-R unimolecular dual agonist, tirzepatide. In addition, a number GLP-1R/GCGR peptides GLP-1R/GCGR/GIPR triagonist entered trials. Other pharmacological approaches chronic management include human monoclonal antibody, bimagrumab which blocks activin II associated growth skeletal muscle, antibody blocking activation GIPR are conjugated peptide agonists (AMG-133), melanocortin-4 receptor setmelanotide use certain inherited obesity conditions. The global demand liraglutide semaglutide as anti-obesity agents led shortage so that their T2D currently being prioritized.
Язык: Английский
Процитировано
71
Journal of Obesity & Metabolic Syndrome, Год журнала: 2023, Номер 32(1), С. 25 - 45
Опубликована: Фев. 8, 2023
The combination of glucagon-like peptide-1 (GLP-1) with other gut hormones including the glucose-dependent insulinotropic polypeptide (GIP) has been explored to complement and enhance further GLP-1 effects on glycemia weight loss.Tirzepatide is first dual GLP-1/GIP receptor co-agonist which approved for treatment type 2 diabetes mellitus (T2DM) based findings from SURPASS program.The trials assessed safety efficacy tirzepatide in people T2DM, monotherapy through insulin add-on global populations, another two dedicated Japanese population.Over periods up 104 weeks, once weekly 5 15 mg reduced glycosylated hemoglobin (1.87% 3.02%), body (5.4 12.9 kg) improved multiple cardiometabolic risk factors (including reduction liver fat, new-onset macroalbuminuria, blood pressure, lipids) across T2DM spectrum.Tirzepatide provided better than placebo commonly used glucose-lowering medications such as semaglutide 1 mg, dulaglutide, degludec, glargine.All doses were well tolerated similar sideeffect profile analogues.In without diabetes, obesity (SURMOUNT-1) resulted substantial reductions (16.5% 22.4%) over 72 weeks.Overall, program SURMOUNT-1 study suggest that marking a new era and/or management agonism hormones.
Язык: Английский
Процитировано
65
Diabetes Research and Clinical Practice, Год журнала: 2023, Номер 202, С. 110773 - 110773
Опубликована: Июнь 24, 2023
Язык: Английский
Процитировано
61
Diabetologia, Год журнала: 2023, Номер 67(3), С. 470 - 482
Опубликована: Дек. 14, 2023
Abstract Aims/hypothesis The aim of this study was to assess the dose–response effects subcutaneous glucagon receptor/glucagon-like peptide-1 receptor dual agonist survodutide (BI 456906) on HbA 1c levels and bodyweight reduction. Methods This Phase II, multicentre, randomised, double-blind, parallel-group, placebo-controlled study, conducted in clinical research centres, assessed participants aged 18–75 years with type 2 diabetes, an level 53–86 mmol/mol (7.0–10.0%) a BMI 25–50 kg/m background metformin therapy. Participants were randomised via interactive response technology receive (up 0.3, 0.9, 1.8 or 2.7 mg once weekly [qw; dose group (DG) 1–4, respectively] 1.2 twice [DG 5 6, respectively]), placebo semaglutide 1.0 qw). all those involved trial conduct/analysis blinded; arm open-label. primary endpoint absolute change from baseline after 16 weeks’ treatment. key secondary relative Results A total 413 (DG1, n =50; DG2, DG3, =52; DG4, DG5, =51; DG6, semaglutide, placebo, =60). full analysis set comprised 411 treated (DG6, =49; =59). Adjusted mean (95% CI) decreased (mean ± SD 64.7±9.2 [8.07±0.84%] treatment: DG1 ( =41), −9.92 (−12.27, −7.56; −0.91% [−1.12, −0.69]); DG2 =46), −15.95 (−18.27, −13.63; −1.46% [−1.67, −1.25]); DG3 =36), −18.72 (−21.15, −16.29; −1.71% [−1.94, −1.49]); DG4 =33), −17.01 (−19.59, −14.43; −1.56% [−1.79, −1.32]); DG5 =44), −17.84 (−20.18, −15.51; −1.63% [−1.85, −1.42]); DG6 −18.38 (−20.90, −15.87; −1.68% [−1.91, −1.45]). reduction similar low-dose (DG2: [−1.46%]; =46) (−16.07 [−1.47%]; =45). Mean dose-dependently up −8.7% (−10.1, −7.3; =37); ≥1.8 qw produced greater reductions than (−5.3% [−6.6, −4.1]; Adverse events (AEs) reported for 77.8% survodutide-treated (mainly gastrointestinal), 52.5% receiving 52.0% semaglutide. Conclusions/interpretation Survodutide reduced treatment diabetes. Dose-related gastrointestinal AEs could be mitigated slower escalations. Trial registration ClinicalTrials.gov NCT04153929 EudraCT 2019-002390-60. Funding Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany. Graphical
Язык: Английский
Процитировано
57
Cell, Год журнала: 2024, Номер 187(15), С. 3789 - 3820
Опубликована: Июль 1, 2024
Язык: Английский
Процитировано
56
Nature, Год журнала: 2024, Номер 629(8014), С. 1133 - 1141
Опубликована: Май 15, 2024
The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel that critical to many processes in the brain. Genome-wide association studies suggest glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis
Язык: Английский
Процитировано
40
Frontiers in Endocrinology, Год журнала: 2024, Номер 15
Опубликована: Апрель 23, 2024
Obesity has become a global epidemic in the modern world, significantly impacting healthcare economy. Lifestyle interventions remain primary approach to managing obesity, with medical therapy considered secondary option, often used conjunction lifestyle modifications. In recent years, there been proliferation of newer therapeutic agents, revolutionizing treatment landscape for obesity. Notably, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, liraglutide, and recently approved dual GLP-1/GIP RAs agonist tirzepatide, have emerged effective medications resulting significant weight loss. These agents not only promote reduction but also improve metabolic parameters, including lipid profiles, glucose levels, central adiposity. On other hand, bariatric surgery demonstrated superior efficacy achieving addressing overall imbalances. However, ongoing technological advancements, is an debate regarding whether personalized medicine, targeting specific components, will shape future developing novel obesity management.
Язык: Английский
Процитировано
20