Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity

New England Journal of Medicine, Journal Year: 2023, Volume and Issue: 389(10), P. 877 - 888

Published: June 23, 2023

Obesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy safety nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron as once-daily oral therapy weight reduction in adults with obesity.In this phase 2, randomized, double-blind trial, we enrolled obesity, or overweight plus at least one weight-related coexisting condition, without diabetes. Participants were randomly assigned to receive four doses (12, 24, 36, 45 mg) placebo once daily 36 weeks. The percentage change from baseline body was assessed week 26 (primary end point) (secondary point).A total 272 participants underwent randomization. At baseline, mean 108.7 kg, body-mass index (the kilograms divided by square height meters) 37.9. 26, ranged -8.6% -12.6% across dose cohorts -2.0% group. -9.4% -14.7% -2.3% placebo. A 10% occurred 46 75% who received orforglipron, compared 9% use led improvement all prespecified cardiometabolic measures. most common adverse events reported gastrointestinal events, which mild moderate, primarily during escalation, discontinuation 10 17% cohorts. profile consistent that GLP-1 class.Daily agonist, associated reduction. Adverse similar those injectable agonists. (Funded Eli Lilly; GZGI ClinicalTrials.gov number, NCT05051579.).

Language: Английский

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Treatment of type 2 diabetes: challenges, hopes, and anticipated successes

The Lancet Diabetes & Endocrinology, Journal Year: 2021, Volume and Issue: 9(8), P. 525 - 544

Published: June 25, 2021

Language: Английский

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Revisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation

Endocrine Reviews, Journal Year: 2020, Volume and Issue: 42(2), P. 101 - 132

Published: Dec. 15, 2020

Abstract Glucagon-like peptide-1 (GLP-1) is produced in gut endocrine cells and the brain, acts through hormonal neural pathways to regulate islet function, satiety, motility, supporting development of GLP-1 receptor (GLP-1R) agonists for treatment diabetes obesity. Classic notions acting as a meal-stimulated hormone from distal are challenged by data production pancreas, importance brain-derived control activity. Moreover, attribution direct vs indirect actions difficult, many tissue cellular targets action do not exhibit robust or detectable GLP-1R expression. Furthermore, reliable detection technically challenging, highly method dependent, subject misinterpretation. Here we revisit GLP-1, scrutinizing key concepts extra-intestinal synthesis secretion. We discuss new insights refining localization expression integrate recent refine our understanding how where inflammation, cardiovascular secretion, gastric emptying, appetite, body weight. These findings update knowledge cell types mechanisms linking endogenous pharmacological activation canonical GLP-1R, metabolic activity multiple organs.

Language: Английский

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Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial

The Lancet Diabetes & Endocrinology, Journal Year: 2022, Volume and Issue: 10(6), P. 418 - 429

Published: April 22, 2022

Language: Английский

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LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(9), P. 1234 - 1247.e9

Published: Aug. 18, 2022

With an increasing prevalence of obesity, there is a need for new therapies to improve body weight management and metabolic health. Multireceptor agonists in development may provide approaches fulfill this unmet medical need. LY3437943 novel triple agonist peptide at the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide (GIPR), glucagon-like peptide-1 (GLP-1R). In vitro, shows balanced GCGR GLP-1R activity but more GIPR activity. obese mice, administration decreased improved glycemic control. Body loss was augmented by addition GCGR-mediated increases energy expenditure GIPR- GLP-1R-driven calorie intake reduction. phase 1 single ascending dose study, showed safety tolerability profile similar other incretins. Its pharmacokinetic supported once-weekly dosing, reduction persisted up day 43 after dose. These findings warrant further clinical assessment LY3437943.

Language: Английский

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GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice

Journal of Clinical Investigation, Journal Year: 2021, Volume and Issue: 131(12)

Published: May 18, 2021

Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor (GLP-1R) agonist, delivered superior glycemic control weight loss compared with GLP-1R agonism in patients type 2 diabetes. However, the mechanism by which tirzepatide improves efficacy how (GIPR) contributes is not fully understood. Here, we show that an effective insulin sensitizer, improving sensitivity obese mice to greater extent than agonism. To determine whether GIPR contributes, effect of WT Glp-1r–null mice. In absence GLP-1R–induced loss, improved enhancing glucose disposal white adipose tissue (WAT). support this, long-acting agonist (LAGIPRA) was found enhance augmenting WAT. Interestingly, LAGIPRA on associated reduced branched-chain amino acids (BCAAs) ketoacids circulation. Insulin sensitization upregulation genes catabolism glucose, lipid, BCAAs brown tissue. Together, our studies weight-dependent -independent manner. These results highlight therapeutic profile dual-receptor agonism, offering mechanistic insights into clinical tirzepatide.

Language: Английский

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Tirzepatide, a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review

Molecules, Journal Year: 2022, Volume and Issue: 27(13), P. 4315 - 4315

Published: July 5, 2022

The prevalence of obesity and diabetes is an increasing global problem, especially in developed countries, referred to as the twin epidemics. As such, advanced treatment approaches are needed. Tirzepatide, known a 'twincretin', 'first-in-class' only dual glucagon-like peptide-1 (GLP-1) glucose-dependent insulinotropic peptide (GIP) receptor agonist, that can significantly reduce glycemic levels improve insulin sensitivity, well reducing body weight by more than 20% improving lipid metabolism. This novel anti-diabetic drug synthetic analog human GIP hormone with C

Language: Английский

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The expanding incretin universe: from basic biology to clinical translation

Diabetologia, Journal Year: 2023, Volume and Issue: 66(10), P. 1765 - 1779

Published: March 28, 2023

Language: Английский

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Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity

New England Journal of Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 16, 2024

BackgroundObesity increases the risk of heart failure with preserved ejection fraction. Tirzepatide, a long-acting agonist glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, causes considerable weight loss, but data are lacking respect to its effects on cardiovascular outcomes.MethodsIn this international, double-blind, randomized, placebo-controlled trial, we randomly assigned, in 1:1 ratio, 731 patients failure, an fraction at least 50%, body-mass index (the kilograms divided by square height meters) 30 receive tirzepatide (up 15 mg subcutaneously once per week) or placebo for 52 weeks. The two primary end points were composite adjudicated death from worsening heart-failure event (assessed time-to-first-event analysis) change baseline weeks Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range 0 100, higher indicating better quality life).ResultsA total 364 assigned group 367 group; median duration follow-up was 104 Adjudicated occurred 36 (9.9%) 56 (15.3%) (hazard 0.62; 95% confidence interval [CI], 0.41 0.95; P=0.026). Worsening events 29 (8.0%) (14.2%) 0.54; CI, 0.34 0.85), 8 (2.2%) 5 (1.4%), respectively 1.58; 0.52 4.83). At weeks, mean (±SD) KCCQ-CSS 19.5±1.2 as compared 12.7±1.3 (between-group difference, 6.9; 3.3 10.6; P<0.001). Adverse (mainly gastrointestinal) leading discontinuation trial drug 23 (6.3%) (1.4%) group.ConclusionsTreatment led lower than improved health status obesity. (Funded Eli Lilly; SUMMIT ClinicalTrials.gov number, NCT04847557.)

Language: Английский

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What is the pipeline for future medications for obesity?

International Journal of Obesity, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 1, 2024

Abstract Obesity is a chronic disease associated with increased risk of obesity-related complications and mortality. Our better understanding the weight regulation mechanisms role gut-brain axis on appetite has led to development safe effective entero-pancreatic hormone-based treatments for obesity such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA). Semaglutide 2.4 mg once weekly, subcutaneously administered GLP-1 RA approved treatment in 2021, results 15–17% mean loss (WL) evidence cardioprotection. Oral are also under early data shows similar WL efficacy semaglutide mg. Looking next generation treatments, combinations other hormones complementary actions and/or synergistic potential (such glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin) investigation enhance cardiometabolic benefits RA. Tirzepatide, dual GLP-1/GIP agonist been glycaemic control type 2 diabetes well management leading up 22.5% phase 3 trials. Other including cagrisema (GLP-1/amylin RA) triple retatrutide (GLP-1/GIP/glucagon have progressed trials suggests that may lead even greater than tirzepatide. Additionally, agents different action (e.g. bimagrumab) improve body composition during clinical We new era pharmacotherapy where approach achieved bariatric surgery. In this review, we present safety pipeline pharmacotherapies focus consider implications challenges bring.

Language: Английский

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