Once-Weekly Semaglutide in Adults with Overweight or Obesity

New England Journal of Medicine, Год журнала: 2021, Номер 384(11), С. 989 - 1002

Опубликована: Фев. 10, 2021

Obesity is a global health challenge with few pharmacologic options. Whether adults obesity can achieve weight loss once-weekly semaglutide at dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

Язык: Английский

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GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art

Molecular Metabolism, Год журнала: 2020, Номер 46, С. 101102 - 101102

Опубликована: Окт. 14, 2020

GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed yield effective compounds/preparations that overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for b.i.d.). To summarize current knowledge about agonist. At present, RAs are injected twice (exenatide b.i.d.), once (lixisenatide and liraglutide), or weekly weekly, dulaglutide, albiglutide, semaglutide). A oral preparation semaglutide, which has demonstrated clinical effectiveness close once-weekly subcutaneous preparation, was recently approved. All share common mechanisms action: augmentation hyperglycemia-induced insulin secretion, suppression glucagon secretion at hyper- euglycemia, deceleration gastric emptying preventing large post-meal glycemic increments, a reduction calorie intake body weight. Short-acting agents b.i.d., lixisenatide) reduced on overnight fasting plasma glucose, but maintain their effect during long-term treatment. Long-acting (liraglutide, exenatide, semaglutide) more profound effects glucose HbA1c, both background glucose-lowering combination basal insulin. Effects decrease over time (tachyphylaxis). Given similar, if not superior, HbA1c additional weight no intrinsic risk hypoglycemic episodes, GLP-1RAs recommended as preferred injectable therapy diabetes, even before However, can be combined (basal) either free- fixed-dose preparations. More agents, particular characterized by greater efficacy respect lowering well Since 2016, several cardiovascular (CV) outcome studies shown effectively prevent CV events such acute myocardial infarction stroke associated mortality. Therefore, guidelines particularly recommend treatment patients pre-existing atherosclerotic vascular disease (for example, previous events). The evidence similar lower-risk subjects is quite strong. sodium/glucose cotransporter-2 (SGLT-2) inhibitor reduces (with mainly driven heart failure complications), individual ischemic complications should guide choice may also help renal diabetes. Other active research areas field definition subgroups within population who benefit from RAs. These include pharmacogenomic approaches characterization non-responders. Novel indications outside 1 neurodegenerative diseases, psoriasis, being explored. Thus, 15 years initial introduction, become well-established class potential development growing impact treating potentially other diseases.

Язык: Английский

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Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity

JAMA, Год журнала: 2021, Номер 325(14), С. 1414 - 1414

Опубликована: Март 23, 2021

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

Язык: Английский

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Anti-obesity drug discovery: advances and challenges

Nature Reviews Drug Discovery, Год журнала: 2021, Номер 21(3), С. 201 - 223

Опубликована: Ноя. 23, 2021

Enormous progress has been made in the last half-century management of diseases closely integrated with excess body weight, such as hypertension, adult-onset diabetes and elevated cholesterol. However, treatment obesity itself proven largely resistant to therapy, anti-obesity medications (AOMs) often delivering insufficient efficacy dubious safety. Here, we provide an overview history AOM development, focusing on lessons learned ongoing obstacles. Recent advances, including increased understanding molecular gut–brain communication, are inspiring pursuit next-generation AOMs that appear capable safely achieving sizeable sustained weight loss. The development therapies loss proved tremendously challenging. Müller et al. drug learned, challenges recent advances field.

Язык: Английский

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Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity

JAMA, Год журнала: 2021, Номер 325(14), С. 1403 - 1403

Опубликована: Фев. 24, 2021

Importance

Weight loss improves cardiometabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective noninvasive weight approaches.

Objective

To compare effects of once-weekly subcutaneous semaglutide, 2.4 mg vs placebo for management as an adjunct to intensive behavioral therapy initial low-calorie diet adults

Design, Setting, Participants

Randomized, double-blind, parallel-group, 68-week, phase 3a study (STEP 3) conducted at 41 sites US from August 2018 April 2020 without diabetes (N = 611) either (body mass index ≥27) plus least 1 comorbidity obesity ≥30).

Interventions

Participants were randomized (2:1) (n 407) 204), both combined a first 8 weeks (ie, 30 counseling visits) during 68 weeks.

Main Outcomes Measures

The co–primary end points percentage change body 5% more baseline by week 68. Confirmatory secondary included losses 10% 15% weight.

Results

Of 611 participants (495 women [81.0%], mean age 46 years [SD, 13], 105.8 kg 22.9], 38.0 6.7]), 567 (92.8%) completed trial, 505 (82.7%) receiving treatment trial end. At 68, estimated was –16.0% semaglutide –5.7% (difference, −10.3 [95% CI, −12.0 −8.6];P < .001). More treated lost (86.6% 47.6%, respectively;P A higher proportion group achieved (75.3% 27.0% 55.8% 13.2%, Gastrointestinal adverse events frequent (82.8%) (63.2%). Treatment discontinued owing these 3.4% 0% participants.

Conclusions Relevance

Among obesity, compared placebo, used diet, resulted significantly greater Further research is needed assess durability findings.

Trial Registration

ClinicalTrials.gov Identifier:NCT03611582

Язык: Английский

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Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes

JAMA, Год журнала: 2022, Номер 327(2), С. 138 - 138

Опубликована: Янв. 11, 2022

InvestigatorsIMPORTANCE Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management.OBJECTIVE To compare the efficacy adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily 3.0 mg (both with diet physical activity), in people overweight or obesity.DESIGN, SETTING, AND PARTICIPANTS Randomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: 11-November 26) to May 2021 (end follow-up: 11) adults body mass index 30 greater 27 1 more weight-related comorbidities, without diabetes (N = 338).INTERVENTIONS Participants were randomized (3:1:3:1) receive (16-week escalation; n 126), matching placebo, (4-week 127), plus activity.Participants unable tolerate could 1.7 mg; participants liraglutide discontinued treatment restart 4-week titration.Placebo groups pooled (n 85). MAIN OUTCOMES MEASURESThe primary end point was percentage change weight, confirmatory secondary points achievement 10% more, 15% 20% loss, assessed week 68.Semaglutide comparisons active double-blinded against matched placebo groups.Comparisons treatments supportive points. RESULTSOf 338 (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean 104.5 [23.8] kg; index, 37.5 [6.8]), 319 (94.4%) completed trial, 271 (80.2%) treatment.The baseline -15.8% -6.4% (difference, -9.4 [95% CI, -12.0 -6.8]; P < .001);weight -1.9%.Participants had significantly odds achieving loss (70.9% 25.6% [odds ratio, 6.3 {95% 3.5 11.2}], 55.6% 12.0% 7.9 4.1 15.4}], 38.5% 6.0% 8.2 19.1}], respectively; all .001).Proportions discontinuing any reason 13.5% 27.6% liraglutide.Gastrointestinal events reported by 84.1% 82.7% liraglutide.CONCLUSIONS RELEVANCE Among obesity diabetes, added counseling activity, resulted 68 weeks.

Язык: Английский

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Contemporary medical, device, and surgical therapies for obesity in adults

The Lancet, Год журнала: 2023, Номер 401(10382), С. 1116 - 1130

Опубликована: Фев. 9, 2023

Язык: Английский

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GLP-1 physiology informs the pharmacotherapy of obesity

Molecular Metabolism, Год журнала: 2021, Номер 57, С. 101351 - 101351

Опубликована: Окт. 8, 2021

Glucagon-like peptide-1 receptor agonists (GLP1RA) augment glucose-dependent insulin release and reduce glucagon secretion gastric emptying, enabling their successful development for the treatment of type 2 diabetes (T2D). These agents also inhibit food intake body weight, fostering investigation GLP1RA obesity. Here I discuss physiology (GLP-1) action in control animals humans, highlighting importance gut vs. brain-derived GLP-1 feeding weight. The widespread distribution function multiple (GLP1R) populations central autonomic nervous system are outlined, pathways controlling energy expenditure preclinical studies reduction both humans is highlighted. relative contributions vagal afferent GLP1R+ physiological anorectic response to compared reviewed. Key data two obesity therapy (liraglutide 3 mg daily semaglutide 2.4 once weekly) discussed. Finally, emerging potentially supporting combination with additional peptide epitopes unimolecular multi-agonists, as well fixed-dose therapies, actions weight highly conserved obese adolescents adults. well-defined mechanisms through a single G protein-coupled receptor, together extensive safety database people T2D, provide reassurance surrounding long-term use these co-morbidities. may be effective conditions associated obesity, such cardiovascular disease non-alcoholic steatohepatitis (NASH). Progressive improvements efficacy suggest that GLP-1-based therapies soon rival bariatric surgery viable options its complications.

Язык: Английский

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Pharmacotherapy of obesity: an update on the available medications and drugs under investigation

EClinicalMedicine, Год журнала: 2023, Номер 58, С. 101882 - 101882

Опубликована: Март 21, 2023

Obesity is an epidemic and a public health threat. Medical weight management remains one of the options for treatment excess recent advances have revolutionized how we treat, more importantly will be treating obesity in near future. Metreleptin Setmelanotide are currently indicated rare syndromes, 5 other medications (orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide) approved non-syndromic obesity. Tirzepatide about to approved, drugs, with exciting novel mechanisms action primarily based on incretins, being investigated different phases clinical trials. The majority these compounds act centrally, reduce appetite increase satiety, secondarily, gastrointestinal tract slow gastric emptying. All anti-obesity improve metabolic parameters, variable potency effects depending specific drug. available data do not support reduction hard cardiovascular outcomes, but it almost certain that such forthcoming very choice medication needs take into consideration patient's biochemical profile, co-morbidities, drug contra-indications, as well expected degree loss improvements cardio-renal risk. It also seen whether precision medicine may offer personalized solutions individuals obesity, represent future medical along development novel, potent, pipeline.FundingNone.

Язык: Английский

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GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects

Frontiers in Endocrinology, Год журнала: 2021, Номер 12

Опубликована: Авг. 23, 2021

Glucagon like peptide-1 (GLP-1) is an incretin secretory molecule. GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss, protection islet β cells, promotion cell proliferation and minimal side effects. Studies have found that GLP-1R distributed on pancreatic other tissues has multiple biological effects, reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism fat deposition. Moreover, GLP-1RAs neuroprotective, anti-infectious, cardiovascular protective, metabolic regulatory exhibiting good application prospects. Growing attention been paid relationship between tumorigenesis, development prognosis patient with T2DM. Here, we reviewed therapeutic effects possible mechanisms action nervous, cardiovascular, endocrine systems correlation metabolism, tumours diseases.

Язык: Английский

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