-
Obesity (Silver Spring, Md.) Mar 2020Previous studies have shown additive weight loss when intensive behavioral therapy (IBT) was combined with weight-loss medication. The present multisite study provides... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Previous studies have shown additive weight loss when intensive behavioral therapy (IBT) was combined with weight-loss medication. The present multisite study provides the first evaluation, in primary care, of the effect of the Centers for Medicare and Medicaid Services-based IBT benefit, delivered alone (with placebo) or in combination with liraglutide 3.0 mg.
METHODS
The Satiety and Clinical Adiposity-Liraglutide Evidence in individuals with and without diabetes (SCALE) IBT was a 56-week, randomized, double-blind, placebo-controlled, multicenter trial in individuals with obesity who received liraglutide 3.0 mg (n = 142) or placebo (n = 140) as an adjunct to IBT.
RESULTS
At week 56, mean weight loss with liraglutide 3.0 mg plus IBT was 7.5% and 4.0% with placebo combined with IBT (estimated treatment difference [95% CI]-3.4% [-5.3% to -1.6%], P = 0.0003). Significantly more individuals on liraglutide 3.0 mg than placebo achieved ≥ 5% weight loss (61.5% vs. 38.8%; odds ratio [OR] 2.5% [1.5% to 4.1%], P = 0.0003), > 10% weight loss (30.5% vs. 19.8%; OR 1.8% [1.0% to 3.1%], P = 0.0469), and > 15% weight loss (18.1% vs. 8.9%; OR 2.3% [1.1% to 4.7%], P = 0.0311). Liraglutide 3.0 mg in combination with IBT was well tolerated, with no new safety signals identified.
CONCLUSIONS
In a primary care setting, Centers for Medicare and Medicaid Services-based IBT produced clinically meaningful weight loss at 56 weeks, enhanced by the addition of liraglutide 3.0 mg.
Topics: Anti-Obesity Agents; Behavior Therapy; Double-Blind Method; Female; Humans; Liraglutide; Male; Middle Aged; Obesity; Treatment Outcome; United States; Weight Loss
PubMed: 32090517
DOI: 10.1002/oby.22726 -
Lancet (London, England) Apr 2017Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes.
METHODS
In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m, or at least 27 kg/m with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219.
FINDINGS
The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13-0·34). Liraglutide induced greater weight loss than placebo at week 160 (-6·1 [SD 7·3] vs -1·9% [6·3]; estimated treatment difference -4·3%, 95% CI -4·9 to -3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group.
INTERPRETATION
In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes.
FUNDING
Novo Nordisk, Denmark.
Topics: Adult; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Liraglutide; Male; Middle Aged; Obesity; Placebos; Prediabetic State; Risk Reduction Behavior; Treatment Outcome; Weight Loss
PubMed: 28237263
DOI: 10.1016/S0140-6736(17)30069-7 -
Hellenic Journal of Cardiology : HJC =... 2019Major cardiovascular (CV) outcome trials with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are currently available. These agonists have proven their CV safety,... (Review)
Review
Major cardiovascular (CV) outcome trials with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are currently available. These agonists have proven their CV safety, in harmony with the US Food and Drug Administration (FDA) recommendation for antidiabetic drugs. The potential cardioprotective effect of incretin-based therapies is attributed to their multiple non-glycaemic actions in the CV system, including changes in insulin resistance, weight loss, reduction in blood pressure, improved lipid profile and direct effects on the heart and vascular endothelium. Liraglutide, semaglutide and albiglutide have been demonstrated to reduce the risk of major adverse cardiac events (MACE), whereas lixisenatide and extended-release exenatide had a neutral effect. Thus, it is conceivable that there are different drug-specific properties across the class of GLP-1 RAs. In this review, we discuss the results of the five recently published randomised CV outcome trials with GLP-1 RAs, along with the potential differences and the pleiotropic actions of these agents on the CV system.
Topics: Aged; Blood Pressure; Cardiovascular Diseases; Cardiovascular System; Case-Control Studies; Diabetes Mellitus, Type 2; Endothelium, Vascular; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin Resistance; Liraglutide; Middle Aged; Randomized Controlled Trials as Topic; Risk Factors; United States; United States Food and Drug Administration; Weight Loss
PubMed: 30528435
DOI: 10.1016/j.hjc.2018.11.008 -
Bioengineered Apr 2022Liver pathological changes are as high as 21%-78% in diabetic patients, and treatment options are lacking. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor that...
Liver pathological changes are as high as 21%-78% in diabetic patients, and treatment options are lacking. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor that is widely used in the clinic and is approved to treat obesity and diabetes. However, the specific protection mechanism needs to be clarified. In the present study, db/db mice were used to simulate Type 2 diabetes mellitus (T2DM), and they were intraperitoneally injected daily with liraglutide (200 μg/kg/d) for 5 weeks. Hepatic function, pathologic changes, oxidative stress, iron levels, and ferroptosis were evaluated. First, liraglutide decreased serum AST and ALT levels, and suppressed liver fibrosis in db/db mice. Second, liraglutide inhibited the ROS production by upregulating SOD, GSH-PX, and GSH activity as well as by downregulating MDA, 4-HNE, and NOX4 expression in db/db mice. Furthermore, liraglutide attenuated iron deposition by decreasing TfR1 expression and increasing FPN1 expression. At the same time, liraglutide decreased ferroptosis by elevating the expression of SLC7A11 and the Nrf2/HO-1/GPX4 signaling pathway in the livers of db/db mice. In addition, liraglutide decreased the high level of labile iron pools (LIPs) and intracellular lipid ROS induced by high glucose in vitro. Therefore, we speculated that liraglutide played a crucial role in reducing iron accumulation, oxidative damage and ferroptosis in db/db mice.
Topics: Animals; Diabetes Mellitus, Type 2; Ferroptosis; Humans; Iron; Liraglutide; Liver; Mice; Reactive Oxygen Species
PubMed: 35311455
DOI: 10.1080/21655979.2022.2051858 -
Obesity (Silver Spring, Md.) Aug 2022This study aimed to determine the effects of a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, and placebo subcutaneously over 16 weeks on... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This study aimed to determine the effects of a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, and placebo subcutaneously over 16 weeks on weight and gastric functions and to evaluate associations of single-nucleotide polymorphisms in GLP1R (rs6923761) and TCF7L2 (rs7903146) with effects of liraglutide.
METHODS
The study conducted a randomized, parallel-group, placebo-controlled, 16-week trial of liraglutide, escalated to 3 mg subcutaneously daily in 136 otherwise healthy adults with obesity. Weight, gastric emptying of solids (GES), gastric volumes, satiation, and body composition measured at baseline and after treatment were compared in two treatment groups using analysis of covariance.
RESULTS
Liraglutide (n = 59) and placebo (n = 65) groups completed treatment. Relative to placebo, liraglutide increased weight loss at 5 and 16 weeks (both p < 0.05), slowed time to half GES (T ) at 5 and 16 weeks (both p < 0.001), and increased fasting gastric volume (p = 0.01) and satiation (p < 0.01) at 16 weeks. GES T was positively correlated with weight loss on liraglutide (both p < 0.001). After 16 weeks of liraglutide, GLP1R rs6923761 (AG/AA vs. GG) was associated with reduced percent body fat (p = 0.062), and TCF7L2 rs7903146 (CC vs. CT/TT) was associated with lower body weight (p = 0.015).
CONCLUSIONS
Liraglutide, 3 mg, induces weight loss with delay in GES T and reduces calorie intake. Slowing GES and variations in GLP1R and TCF7L2 are associated with liraglutide effects in obesity.
Topics: Adult; Double-Blind Method; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Pharmacogenetics; Weight Loss
PubMed: 35894080
DOI: 10.1002/oby.23481 -
Reviews in Endocrine & Metabolic... Aug 2023Emerging evidence suggests that treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) could be an interesting treatment strategy to reduce neurological... (Review)
Review
Emerging evidence suggests that treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) could be an interesting treatment strategy to reduce neurological complications such as stroke, cognitive impairment, and peripheral neuropathy. We performed a systematic review to examine the evidence concerning the effects of GLP-1 RAs on neurological complications of diabetes. The databases used were Pubmed, Scopus and Cochrane. We selected clinical trials which analysed the effect of GLP-1 RAs on stroke, cognitive impairment, and peripheral neuropathy. We found a total of 19 studies: 8 studies include stroke or major cardiovascular events, 7 involve cognitive impairment and 4 include peripheral neuropathy. Semaglutide subcutaneous and dulaglutide reduced stroke cases. Liraglutide, albiglutide, oral semaglutide and efpeglenatide, were not shown to reduce the number of strokes but did reduce major cardiovascular events. Exenatide, dulaglutide and liraglutide improved general cognition but no significant effect on diabetic peripheral neuropathy has been reported with GLP-1 RAs. GLP-1 RAs are promising drugs that seem to be useful in the reduction of some neurological complications of diabetes. However, more studies are needed.
Topics: Humans; Hypoglycemic Agents; Liraglutide; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide 1; Cardiovascular Diseases; Stroke; Diabetes Complications
PubMed: 37231200
DOI: 10.1007/s11154-023-09807-3 -
Journal of Endocrinological... Sep 2023Despite Polycystic Ovary Syndrome (PCOS) is a very prevalent disorder among women of reproductive age, there is widespread agreement that until now, no pharmacological... (Review)
Review
Despite Polycystic Ovary Syndrome (PCOS) is a very prevalent disorder among women of reproductive age, there is widespread agreement that until now, no pharmacological options are available to tackle the entire spectrum of clinical manifestations encountered in the clinical practice. Obesity and insulin resistance, which commonly characterized this syndrome, prompted the design of studies investigating the effects of glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RA) in PCOS. Indeed, a very impressive number of randomized controlled clinical trials (RCTs) and systematic reviews provided robust evidence on the effectiveness of GLP-1RA in PCOS as a new, appealing approach, producing both satisfactory and permanent weight loss, and improvement of insulin resistance at the same time. However, most of the subjects included in the RCTs are PCOS patients with obesity/overweight, whereas a portion of PCOS women, which can even reach 50%, might present a lean phenotype. Moreover, some benefits on clinical and metabolic features of PCOS may not have fully emerged due to the low or medium doses employed in the vast majority of the current studies. Thus, pitfalls in the methodology of these studies have led sometimes to misleading results. In addition, some aspects of GLP-1 beyond weight loss, such as preclinical evidence on GLP-1 effects in directly modulating the hypothalamus-pituitary-gonadal axis, or the effects of GLP-1RA on clinical and biochemical expression of hyperandrogenism, still deserve a greater insight, especially in light of a possible therapeutic use in PCOS women independently of obesity. Aim of this review is to further unravel the possible role of GLP-1 in PCOS pathogenesis, tempting to provide additional supports to the rationale of treatment with GLP-1RA in the management of PCOS also independent of weight loss. For this purpose, the outcomes of RCTs investigating in PCOS the anthropometric and metabolic changes have been treated separately to better underpin the effects of GLP-1 RA, in particular liraglutide, beyond weight loss.
Topics: Humans; Female; Liraglutide; Polycystic Ovary Syndrome; Insulin Resistance; Body Weight; Obesity; Glucagon-Like Peptide 1; Weight Loss
PubMed: 37093453
DOI: 10.1007/s40618-023-02084-6 -
Frontiers in Immunology 2022Ischemia-reperfusion injury (IRI) is a common complication associated with liver surgery, and macrophages play an important role in hepatic IRI. Liraglutide, a...
Ischemia-reperfusion injury (IRI) is a common complication associated with liver surgery, and macrophages play an important role in hepatic IRI. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog primarily used to treat type 2 diabetes and obesity, regulates intracellular calcium homeostasis and protects the cardiomyocytes from injury; however, its role in hepatic IRI is not yet fully understood. This study aimed to investigate whether liraglutide can protect the liver from IRI and determine the possible underlying mechanisms. Our results showed that liraglutide pretreatment significantly alleviated the liver damage caused by ischemia-reperfusion (I/R), as evidenced by H&E staining, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and TUNEL staining. Furthermore, the levels of inflammatory cytokines elicited by I/R were distinctly suppressed by liraglutide pretreatment, accompanied by significant reduction in TNF-α, IL-1β, and IL-6 levels. Furthermore, pretreatment with liraglutide markedly inhibited macrophage type I (M1) polarization during hepatic IRI, as revealed by the significant reduction in CD68 levels in Kupffer cells (KCs) detected flow cytometry. However, the protective effects of liraglutide on hepatic IRI were partly diminished in GLP-1 receptor-knockout (GLP-1R) mice. Furthermore, in an study, we assessed the role of liraglutide in macrophage polarization by examining the expression profiles of M1 in bone marrow-derived macrophages (BMDMs) from GLP-1R and C57BL/6J mice. Consistent with the results of the study, liraglutide treatment attenuated the LPS-induced M1 polarization and reduced the expression of M1 markers. However, the inhibitory effect of liraglutide on LPS-induced M1 polarization was largely abolished in BMDMs from GLP-1R mice. Collectively, our study indicates that liraglutide can ameliorate hepatic IRI by inhibiting macrophage polarization towards an inflammatory phenotype GLP-1R. Its protective effect against liver IRI suggests that liraglutide may serve as a potential drug for the clinical treatment of liver IRI.
Topics: Animals; Diabetes Mellitus, Type 2; Lipopolysaccharides; Liraglutide; Liver; Macrophages; Mice; Mice, Inbred C57BL; Reperfusion Injury
PubMed: 35450076
DOI: 10.3389/fimmu.2022.869050 -
International Journal of Obesity (2005) Aug 2016Obesity is strongly associated with prevalence of obstructive sleep apnea (OSA), and weight loss has been shown to reduce disease severity. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Obesity is strongly associated with prevalence of obstructive sleep apnea (OSA), and weight loss has been shown to reduce disease severity.
OBJECTIVE
To investigate whether liraglutide 3.0 mg reduces OSA severity compared with placebo using the primary end point of change in apnea-hypopnea index (AHI) after 32 weeks. Liraglutide's weight loss efficacy was also examined.
SUBJECTS/METHODS
In this randomized, double-blind trial, non-diabetic participants with obesity who had moderate (AHI 15-29.9 events h(-1)) or severe (AHI ⩾30 events h(-1)) OSA and were unwilling/unable to use continuous positive airway pressure therapy were randomized for 32 weeks to liraglutide 3.0 mg (n=180) or placebo (n=179), both as adjunct to diet (500 kcal day(-1) deficit) and exercise. Baseline characteristics were similar between groups (mean age 48.5 years, males 71.9%, AHI 49.2 events h(-1), severe OSA 67.1%, body weight 117.6 kg, body mass index 39.1 kg m(-2), prediabetes 63.2%, HbA1c 5.7%).
RESULTS
After 32 weeks, the mean reduction in AHI was greater with liraglutide than with placebo (-12.2 vs -6.1 events h(-1), estimated treatment difference: -6.1 events h(-1) (95% confidence interval (CI), -11.0 to -1.2), P=0.0150). Liraglutide produced greater mean percentage weight loss compared with placebo (-5.7% vs -1.6%, estimated treatment difference: -4.2% (95% CI, -5.2 to -3.1%), P<0.0001). A statistically significant association between the degree of weight loss and improvement in OSA end points (P<0.01, all) was demonstrated post hoc. Greater reductions in glycated hemoglobin (HbA1c) and systolic blood pressure (SBP) were seen with liraglutide versus placebo (both P<0.001). The safety profile of liraglutide 3.0 mg was similar to that seen with doses ⩽1.8 mg.
CONCLUSIONS
As an adjunct to diet and exercise, liraglutide 3.0 mg was generally well tolerated and produced significantly greater reductions than placebo in AHI, body weight, SBP and HbA1c in participants with obesity and moderate/severe OSA. The results confirm that weight loss improves OSA-related parameters.
Topics: Adolescent; Adult; Anti-Obesity Agents; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Obesity; Polysomnography; Prospective Studies; Sleep Apnea, Obstructive; Treatment Outcome; United States; Weight Loss; Young Adult
PubMed: 27005405
DOI: 10.1038/ijo.2016.52 -
Hormone and Metabolic Research =... Jul 2022Aim To determine the antiobesity effect and safety of glucagon-like peptide-1 receptor agonist (GLP-1RA) including liraglutide, exenatide and semaglutide treatment in... (Meta-Analysis)
Meta-Analysis
Aim To determine the antiobesity effect and safety of glucagon-like peptide-1 receptor agonist (GLP-1RA) including liraglutide, exenatide and semaglutide treatment in overweight/obese patients without diabetes. The random-effect model was used to pool data extracted from included literatures. The weighted mean difference (WMD), odds ratio and 95% confidence interval (CI) were used to present the meta-analysis results (PROSPERO registration number: CRD 42020173199). The sources of intertrial heterogeneity, bias and the robustness of results were evaluated by subgroup analysis, sensitivity analysis and regression analysis, respectively. A total of 24 RCTs were recruited in the present analysis which included 5867 patients. The results showed that the treatment of overweight/obese patients without diabetes with GLP-1RAs including liraglutide, exenatide and semaglutide significantly achieved greater weight loss than placebo [WMD=-5.39, 95% CI (-6.82, -3.96)] and metformin [WMD=-5.46, 95% CI (-5.87, -5.05)]. The subgroup analysis showed that semaglutide displayed the most obvious antiobesity effect in terms of weight loss, the reduction of body mass index (BMI) and waist circumference (WC). However, GLP-1RAs treatments had more gastrointestinal adverse events (such as nausea and vomiting) than placebo and Met. The subgroup analysis also represented that semaglutide displayed the lowest risk of gastrointestinal adverse events among three kinds of GLP-1RAs. Our meta-analysis demonstrated that GLP-1RA had a superior antiobesity effect than placebo/Met in overweight/obese patients without diabetes in terms of body weight, BMI, and WC, especially for semaglutide, which had more obvious antiobesity effect and lower GI adverse events than liraglutide and exenatide.
Topics: Anti-Obesity Agents; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Weight Loss
PubMed: 35512849
DOI: 10.1055/a-1844-1176