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JAMA Jan 2022Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management.
OBJECTIVE
To compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (N = 338).
INTERVENTIONS
Participants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment and could restart the 4-week titration. Placebo groups were pooled (n = 85).
MAIN OUTCOMES AND MEASURES
The primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label, with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end points.
RESULTS
Of 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD] body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was -15.8% with semaglutide vs -6.4% with liraglutide (difference, -9.4 percentage points [95% CI, -12.0 to -6.8]; P < .001); weight change with pooled placebo was -1.9%. Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P < .001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide.
CONCLUSIONS AND RELEVANCE
Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04074161.
Topics: Body Weight; Diabetes Mellitus; Diet Therapy; Drug Administration Schedule; Exercise; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Liraglutide; Male; Middle Aged; Obesity; Odds Ratio; Overweight; Patient Dropouts; Placebos; Treatment Outcome; United States; Weight Loss
PubMed: 35015037
DOI: 10.1001/jama.2021.23619 -
The New England Journal of Medicine Jul 2016The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. (Randomized Controlled Trial)
Randomized Controlled Trial
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.).
Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Gastrointestinal Diseases; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Myocardial Infarction; Stroke; Treatment Outcome
PubMed: 27295427
DOI: 10.1056/NEJMoa1603827 -
Lancet (London, England) Feb 2016Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis.
METHODS
This multicentre, double-blinded, randomised, placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide (1·8 mg daily) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis. Patients were randomly assigned (1:1) using a computer-generated, centrally administered procedure, stratified by trial centre and diabetes status. The trial was designed using A'Hern's single-group method, which required eight (38%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinically significant. Patients, investigators, clinical trial site staff, and pathologists were masked to treatment assignment throughout the study. The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment (48 weeks), as assessed centrally by two independent pathologists. Analysis was done by intention-to-treat analysis, which included all patients who underwent end-of-treatment biopsy. The trial was registered with ClinicalTrials.gov, number NCT01237119.
FINDINGS
Between Aug 1, 2010, and May 31, 2013, 26 patients were randomly assigned to receive liraglutide and 26 to placebo. Nine (39%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two (9%) of 22 such patients in the placebo group (relative risk 4·3 [95% CI 1·0-17·7]; p=0·019). Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0·2 [0·1-1·0]; p=0·04). Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the two treatment groups for all organ classes and symptoms, with the exception of gastrointestinal disorders in 21 (81%) of 23 patients in the liraglutide group and 17 (65%) of 22 patients in the placebo group, which included diarrhoea (ten [38%] patients in the liraglutide group vs five [19%] in the placebo group), constipation (seven [27%] vs none), and loss of appetite (eight [31%] vs two [8%]).
INTERPRETATION
Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies.
FUNDING
Wellcome Trust, National Institute of Health Research, and Novo Nordisk.
Topics: Adolescent; Adult; Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Incretins; Injections, Subcutaneous; Liraglutide; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Treatment Outcome; Young Adult
PubMed: 26608256
DOI: 10.1016/S0140-6736(15)00803-X -
Molecular Metabolism Mar 2022Glucagon-like peptide-1 receptor agonists (GLP1RA) augment glucose-dependent insulin release and reduce glucagon secretion and gastric emptying, enabling their... (Review)
Review
BACKGROUND
Glucagon-like peptide-1 receptor agonists (GLP1RA) augment glucose-dependent insulin release and reduce glucagon secretion and gastric emptying, enabling their successful development for the treatment of type 2 diabetes (T2D). These agents also inhibit food intake and reduce body weight, fostering investigation of GLP1RA for the treatment of obesity.
SCOPE OF REVIEW
Here I discuss the physiology of Glucagon-like peptide-1 (GLP-1) action in the control of food intake in animals and humans, highlighting the importance of gut vs. brain-derived GLP-1 for the control of feeding and body weight. The widespread distribution and function of multiple GLP-1 receptor (GLP1R) populations in the central and autonomic nervous system are outlined, and the importance of pathways controlling energy expenditure in preclinical studies vs. reduction of food intake in both animals and humans is highlighted. The relative contributions of vagal afferent pathways vs. GLP1R+ populations in the central nervous system for the physiological reduction of food intake and the anorectic response to GLP1RA are compared and reviewed. Key data enabling the development of two GLP1RA for obesity therapy (liraglutide 3 mg daily and semaglutide 2.4 mg once weekly) are discussed. Finally, emerging data potentially supporting the combination of GLP-1 with additional peptide epitopes in unimolecular multi-agonists, as well as in fixed-dose combination therapies, are highlighted.
MAJOR CONCLUSIONS
The actions of GLP-1 to reduce food intake and body weight are highly conserved in obese animals and humans, in both adolescents and adults. The well-defined mechanisms of GLP-1 action through a single G protein-coupled receptor, together with the extensive safety database of GLP1RA in people with T2D, provide reassurance surrounding the long-term use of these agents in people with obesity and multiple co-morbidities. GLP1RA may also be effective in conditions associated with obesity, such as cardiovascular disease and non-alcoholic steatohepatitis (NASH). Progressive improvements in the efficacy of GLP1RA suggest that GLP-1-based therapies may soon rival bariatric surgery as viable options for the treatment of obesity and its complications.
Topics: Adolescent; Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Liraglutide; Obesity
PubMed: 34626851
DOI: 10.1016/j.molmet.2021.101351 -
JAMA Jun 2016Five medications have been approved for the management of obesity, but data on comparative effectiveness are limited. (Meta-Analysis)
Meta-Analysis Review
IMPORTANCE
Five medications have been approved for the management of obesity, but data on comparative effectiveness are limited.
OBJECTIVE
To compare weight loss and adverse events among drug treatments for obesity using a systematic review and network meta-analysis.
DATA SOURCES
MEDLINE, EMBASE, Web of Science, Scopus, and Cochrane Central from inception to March 23, 2016; clinical trial registries.
STUDY SELECTION
Randomized clinical trials conducted among overweight and obese adults treated with US Food and Drug Administration-approved long-term weight loss agents (orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, or liraglutide) for at least 1 year compared with another active agent or placebo.
DATA EXTRACTION AND SYNTHESIS
Two investigators identified studies and independently abstracted data using a predefined protocol. A Bayesian network meta-analysis was performed and relative ranking of agents was assessed using surface under the cumulative ranking (SUCRA) probabilities. Quality of evidence was assessed using GRADE criteria.
MAIN OUTCOMES AND MEASURES
Proportions of patients with at least 5% weight loss and at least 10% weight loss, magnitude of decrease in weight, and discontinuation of therapy because of adverse events at 1 year.
RESULTS
Twenty-eight randomized clinical trials with 29 018 patients (median age, 46 years; 74% women; median baseline body weight, 100.5 kg; median baseline body mass index, 36.1) were included. A median 23% of placebo participants had at least 5% weight loss vs 75% of participants taking phentermine-topiramate (odds ratio [OR], 9.22; 95% credible interval [CrI], 6.63-12.85; SUCRA, 0.95), 63% of participants taking liraglutide (OR, 5.54; 95% CrI, 4.16-7.78; SUCRA, 0.83), 55% taking naltrexone-bupropion (OR, 3.96; 95% CrI, 3.03-5.11; SUCRA, 0.60), 49% taking lorcaserin (OR, 3.10; 95% CrI, 2.38-4.05; SUCRA, 0.39), and 44% taking orlistat (OR, 2.70; 95% CrI, 2.34-3.09; SUCRA, 0.22). All active agents were associated with significant excess weight loss compared with placebo at 1 year-phentermine-topiramate, 8.8 kg (95% CrI, -10.20 to -7.42 kg); liraglutide, 5.3 kg (95% CrI, -6.06 to -4.52 kg); naltrexone-bupropion, 5.0 kg (95% CrI, -5.94 to -3.96 kg); lorcaserin, 3.2 kg (95% CrI, -3.97 to -2.46 kg); and orlistat, 2.6 kg (95% CrI, -3.04 to -2.16 kg). Compared with placebo, liraglutide (OR, 2.95; 95% CrI, 2.11-4.23) and naltrexone-bupropion (OR, 2.64; 95% CrI, 2.10-3.35) were associated with the highest odds of adverse event-related treatment discontinuation. High attrition rates (30%-45% in all trials) were associated with lower confidence in estimates.
CONCLUSIONS AND RELEVANCE
Among overweight or obese adults, orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, and liraglutide, compared with placebo, were each associated with achieving at least 5% weight loss at 52 weeks. Phentermine-topiramate and liraglutide were associated with the highest odds of achieving at least 5% weight loss.
Topics: Anti-Obesity Agents; Bayes Theorem; Benzazepines; Drug Combinations; Female; Fructose; Humans; Lactones; Liraglutide; Male; Middle Aged; Naltrexone; Obesity; Orlistat; Phentermine; Randomized Controlled Trials as Topic; Topiramate; Weight Loss
PubMed: 27299618
DOI: 10.1001/jama.2016.7602 -
Advances in Therapy Jun 2021Obesity is a chronic disease associated with many complications. Weight loss of 5-15% can improve many obesity-related complications. Despite the benefits of weight... (Review)
Review
Obesity is a chronic disease associated with many complications. Weight loss of 5-15% can improve many obesity-related complications. Despite the benefits of weight reduction, there are many challenges in losing weight and maintaining long-term weight loss. Pharmacotherapy can help people with obesity achieve and maintain their target weight loss, thereby reducing the risk of obesity-related complications. The prevalence of obesity in the USA has been increasing over the past few decades, and despite the availability of approved anti-obesity medications (AOMs), people with obesity may not be accessing or receiving treatment at levels consistent with the disease prevalence. Reasons for low levels of initiation and long-term use of AOMs may include reluctance of public health and medical organizations to recognize obesity as a disease, lack of reimbursement, provider inexperience, and misperceptions about the efficacy and safety of available treatments. This article aims to inform primary care providers about the mechanism of action of one class of AOMs, glucagon-like peptide 1 receptor agonists (GLP-1RAs), in weight loss and longer-term maintenance of weight loss, and the efficacy and safety of this treatment class. GLP-1RA therapy was initially developed to treat type 2 diabetes. Owing to their effectiveness in reducing body weight, once-daily subcutaneous administration of liraglutide 3.0 mg has been approved, and once-weekly subcutaneous administration of semaglutide 2.4 mg is being investigated in phase III trials, for obesity management. Considerations regarding adverse effects and contraindications for different drug classes are provided to help guide treatment decision-making when considering pharmacotherapy for weight management in patients with obesity.
Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Pharmaceutical Preparations; Weight Loss
PubMed: 33977495
DOI: 10.1007/s12325-021-01710-0 -
Drug Design, Development and Therapy 2015The prevalence of obesity worldwide has nearly doubled since 1980 with current estimates of 2.1 billion in 2013. Overweight and obesity lead to numerous adverse... (Review)
Review
The prevalence of obesity worldwide has nearly doubled since 1980 with current estimates of 2.1 billion in 2013. Overweight and obesity lead to numerous adverse conditions including type 2 diabetes, cardiovascular disease, stroke, and certain cancers. The worldwide spread of obesity and associated comorbidities not only threatens quality of life but also presents a significant economic burden. While bariatric surgery has proven to be a viable treatment option for the morbidly obese, there is clearly a need for less invasive alternatives. Recent research has suggested that long-acting analogs of the gut hormone, glucagon-like peptide 1 (GLP-1), may have potential as an antiobesity treatment. The GLP-1 receptor agonist, liraglutide (trade name Saxenda), was recently approved by the US Food and Drug Administration as an obesity treatment option and shown in clinical trials to be effective in reducing and sustaining body weight loss. This review presents the basis for GLP-1-based therapies with a specific focus on animal and human studies examining liraglutide's effects on food intake and body weight.
Topics: Animals; Glucagon-Like Peptide-1 Receptor; Humans; Liraglutide; Obesity
PubMed: 25848222
DOI: 10.2147/DDDT.S58459 -
JAMA Nov 2023
Topics: Humans; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Hypoglycemic Agents; Liraglutide; Weight Loss; Anti-Obesity Agents; Overweight; Gastrointestinal Diseases
PubMed: 37796527
DOI: 10.1001/jama.2023.19574 -
Cell Metabolism Jul 2022Liraglutide, an anti-diabetic drug and agonist of the glucagon-like peptide one receptor (GLP1R), has recently been approved to treat obesity in individuals with or...
Liraglutide, an anti-diabetic drug and agonist of the glucagon-like peptide one receptor (GLP1R), has recently been approved to treat obesity in individuals with or without type 2 diabetes. Despite its extensive metabolic benefits, the mechanism and site of action of liraglutide remain unclear. Here, we demonstrate that liraglutide is shuttled to target cells in the mouse hypothalamus by specialized ependymoglial cells called tanycytes, bypassing the blood-brain barrier. Selectively silencing GLP1R in tanycytes or inhibiting tanycytic transcytosis by botulinum neurotoxin expression not only hampers liraglutide transport into the brain and its activation of target hypothalamic neurons, but also blocks its anti-obesity effects on food intake, body weight and fat mass, and fatty acid oxidation. Collectively, these striking data indicate that the liraglutide-induced activation of hypothalamic neurons and its downstream metabolic effects are mediated by its tanycytic transport into the mediobasal hypothalamus, strengthening the notion of tanycytes as key regulators of metabolic homeostasis.
Topics: Animals; Blood-Brain Barrier; Diabetes Mellitus, Type 2; Ependymoglial Cells; Hypothalamus; Liraglutide; Mice; Obesity
PubMed: 35716660
DOI: 10.1016/j.cmet.2022.06.002 -
Clinical Pharmacokinetics Jun 2016Liraglutide is an acylated glucagon-like peptide-1 analogue with 97 % amino acid homology with native glucagon-like peptide-1 and greatly protracted action. It is... (Review)
Review
Liraglutide is an acylated glucagon-like peptide-1 analogue with 97 % amino acid homology with native glucagon-like peptide-1 and greatly protracted action. It is widely used for the treatment of type 2 diabetes mellitus, and administered by subcutaneous injection once daily. The pharmacokinetic properties of liraglutide enable 24-h exposure coverage, a requirement for 24-h glycaemic control with once-daily dosing. The mechanism of protraction relates to slowed release from the injection site, and a reduced elimination rate owing to metabolic stabilisation and reduced renal filtration. Drug exposure is largely independent of injection site, as well as age, race and ethnicity. Increasing body weight and male sex are associated with reduced concentrations, but there is substantial overlap between subgroups; therefore, dose escalation should be based on individual treatment outcome. Exposure is reduced with mild, moderate or severe renal or hepatic impairment. There are no clinically relevant changes in overall concentrations of various drugs (e.g. paracetamol, atorvastatin, griseofulvin, digoxin, lisinopril and oral combination contraceptives) when co-administered with liraglutide. Pharmacodynamic studies show multiple beneficial actions with liraglutide, including improved fasting and postprandial glycaemic control (mediated by increased insulin and reduced glucagon levels and minor delays in gastric emptying), reduced appetite and energy intake, and effects on postprandial lipid profiles. The counter-regulatory hormone response to hypoglycaemia is largely unaltered. The effects of liraglutide on insulin and glucagon secretion are glucose dependent, and hence the risk of hypoglycaemia is low. The pharmacokinetic and pharmacodynamic properties of liraglutide make it an important treatment option for many patients with type 2 diabetes.
Topics: Area Under Curve; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Interactions; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Lipids; Liraglutide; Liver Failure; Renal Insufficiency; Sex Factors
PubMed: 26597252
DOI: 10.1007/s40262-015-0343-6