Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss.
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ABSTRACT:
SUBMITTER: Sodhi M
PROVIDER: S-EPMC10557026 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss.
Sodhi Mohit M Rezaeianzadeh Ramin R Kezouh Abbas A Etminan Mahyar M
JAMA 20231101 18
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Project description:Gastrointestinal (GI) adverse events (AEs) are the most common AEs with glucagon-like peptide-1 receptor agonists (GLP-1RAs). Weight loss (WL) is slightly greater in people who experience GI AEs than those who do not. A previous mediation analysis of the SUSTAIN 1-5 trials indicated minor contribution of nausea/vomiting to the greater WL with once-weekly semaglutide versus comparators. Semaglutide demonstrated superior glycated hemoglobin and body weight (BW) reductions versus other GLP-1RAs in SUSTAIN 3 (versus exenatide extended release 2.0 mg), SUSTAIN 7 (versus dulaglutide) and SUSTAIN 10 (liraglutide 1.2 mg). The objective of this analysis was to assess if significantly greater WL with semaglutide versus other GLP-1RAs is mediated by nausea/vomiting and other GI AEs (diarrhea, constipation, dyspepsia) during dose escalation (baseline to week 12, when GI AEs are generally most prevalent) and from baseline to end of treatment (EOT: week 56 (SUSTAIN 3), 40 (SUSTAIN 7) or 30 (SUSTAIN 10)). Subjects within trials were subdivided into those who reported (yes/no) nausea/vomiting or any other GI AE. Change from baseline in BW was assessed within each trial and subgroup. A mediation analysis separated WL into direct or indirect (mediated by GI AEs) effects. From baseline to week 12 or EOT, the nausea/vomiting-mediated difference in WL was, respectively: 0.05 or 0.09 kg of 3.78 kg at EOT (SUSTAIN 3); 0.06 or 0.03 kg of 2.26 kg at EOT (low-dose comparison) and 0.08 or 0.04 kg of 3.55 kg at EOT (high-dose comparison) (SUSTAIN 7) and 0.05 or 0.09 kg of 3.82 kg at EOT (SUSTAIN 10). In SUSTAIN 3, 7 and 10, nausea/vomiting by week 12 (end of dose escalation) or throughout treatment contributed minimally (<0.1 kg) to the superior WL with semaglutide versus GLP-1RA comparators at EOT.
| S-EPMC7594204 | biostudies-literature
Project description:AimsTo characterize gastrointestinal adverse events (AEs) with different glucagon-like peptide-1 receptor agonists (GLP-1RAs).MethodsTwo retrospective intention-to-treat analyses of 6-month patient-level data were conducted. Data from three studies comparing exenatide once weekly (n = 617) with exenatide twice daily (n = 606) were pooled, and one (DURATION-6) comparing exenatide once weekly (n = 461) with liraglutide (n = 450) was analysed separately. Patient-reported gastrointestinal AEs were classified as upper or lower, AE incidences and timing were determined, subgroups were analysed, and associations of gastrointestinal AEs with efficacy were examined.ResultsNausea was the most common gastrointestinal AE for all treatments. Fewer exenatide once-weekly-treated vs exenatide twice-daily- or liraglutide-treated patients reported gastrointestinal AEs (34% vs 45% and 25% vs 41%, respectively; both P < .0001). Fewer exenatide once-weekly-treated patients reported upper plus lower events than liraglutide-treated patients ( P < .001); the difference between exenatide once weekly and twice daily was not significant. Within each group, more women than men reported gastrointestinal AEs. Events occurrred early and were predominantly mild. Glycated haemoglobin reductions were similar for patients with or without gastrointestinal AEs. Weight loss was greater for patients with gastrointestinal AEs with exenatide once weekly and exenatide twice daily ( P < .05); no difference was observed in DURATION-6.ConclusionsGastrointestinal AEs were less frequent with exenatide once weekly vs exenatide twice daily or liraglutide, and combined upper and lower events occurred less often. Gastrointestinal AEs were typically mild and occurred early. Gastrointestinal AEs did not affect glycaemic control but may be associated with greater weight loss.
| S-EPMC5412849 | biostudies-literature
Project description:IntroductionGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a new class of drugs used in the treatment of type 2 diabetes mellitus (T2DM). Gastrointestinal (GI) adverse events (AEs) are the most frequently reported treatment-related AEs for GLP-1 RAs. We aim to evaluate the effect of GLP-1 RAs on the incidence of GI AEs of T2DM.Materials and methodsThe overview of the GI events of GLP-1 RAs has been performed on relevant publications through the literature search, such as MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov The manufacturer was contacted regarding unpublished data. We analyzed direct and indirect comparisons of different treatments using Bayesian network meta-analysis.ResultsTaspoglutide 30 mg once weekly (TAS30QW) and lixisenatide 30 ?g twice daily (LIX30BID) were ranked the top two drugs in terms of GI AEs versus placebo. The odds ratios of nausea and vomiting for TAS30QW were 11.8 (95% confidence interval [CI], 2.89, 46.9) and 51.7 (95% CI, 7.07, 415), respectively, and that of diarrhea was 4.93 (95% CI, 1.75, 14.7) for LIX30BID.ConclusionsOur study found all GLP-1 RA dose regimens significantly increased the incidence of GI AEs, compared with placebo or conventional treatment. The occurrence of GI AEs was different with diverse dose regimens of GLP-1 RAs. TAS30QW had the maximum probability to occur nausea and vomiting, whereas LIX30BID had the maximum probability to cause development of diarrhea versus other treatments.
| S-EPMC4290796 | biostudies-literature
Project description:BackgroundComparative effectiveness of 7 glucagon-like peptide 1 (GLP-1) agents on weight loss (WL) in obesity remains unknown.MethodsWe performed a systematic review, network meta-analysis (NMA) utilizing the following data sources: MEDLINE, EMBASE, Scopus, Cochrane Central and clinical trial registries, from inception to March 2, 2021. The prespecified criteria for study inclusion were randomized clinical trials (RCTs) of ≥12 weeks' duration. The data appraisal and extraction were performed by two investigators independently, using the published reports. The main outcomes and statistical methods were weight loss over placebo (WLOP) and adverse events (AEs) among GLP-1 agents using random-effects NMA (frequentist approach); relative ranking using surface under the cumulative ranking (SUCRA) method and certainty of evidence using grading of recommendations, assessment, development and evaluations (GRADE).Findings64 RCTs (from 2004 to 2021) included 27018 patients (median of age, 55.1 years old; 57.4% women; baseline weight 94.8kg and BMI 33.0kg/m2; trial duration 26 weeks). Direct meta-analysis showed significant WLOP with: -1.44kg (95% CI, -2.14 to -0.74) with dulaglutide ≥1.5 mg; -1.82kg (-2.42 to -1.23) with exenatide immediate release (IR); -2.20kg (-4.31 to -0.08) with exenatide extended release (ER); -3.20kg (-6.53 to 0.15) with efpeglenatide; -2.72kg (-3.35 to -2.09) with liraglutide ≤1.8mg; -4.49kg (-5.26 to -3.72) with liraglutide >1.8mg; -0.62kg (-1.22 to -0.02) with lixisenatide; -4.33kg (-5.71 to -3.00) with semaglutide SQ <2.4mg; -9.88kg (-13.17 to -6.59) with semaglutide SQ 2.4mg; -2.73kg (-4.81 to -0.65) with semaglutide oral; and -1.71kg (-2.64 to -0.78) with taspoglutide. Highest WLOP were with semaglutide SQ 2.4mg and <2.4mg, and liraglutide >1.8mg (SUCRAs 100, 86.1, 82.8 respectively). Highest SUCRAs for discontinuation due to AEs were with taspoglutide and liraglutide >1.8mg. Risk of bias was high or unclear for random sequence generation (29.7%), allocation concealment (26.6%), and incomplete outcome data (26.6%). Heterogeneity (I2 >50%) in WL and AEs reflected magnitude, not direction of effect.
| S-EPMC8633575 | biostudies-literature
Project description: Not available
| S-EPMC9544962 | biostudies-literature
Project description:AimsGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the recommended first injectable therapy in type 2 diabetes. However, long-term persistence is suboptimal and partly attributable to gastrointestinal tolerability, particularly during initiation/escalation. Gradual titration of fixed-ratio combination GLP-1 RA/insulin therapies may improve GLP-1 RA gastrointestinal tolerability. We compared gastrointestinal adverse event (AE) rates for iGlarLixi versus GLP-1 RAs during the first 12 weeks of therapy, including a sensitivity analysis with IDegLira.Materials and methodsThe PICO framework was used to identify studies from MEDLINE, EMBASE and CENTRAL searches using a proprietary, web-based, standardized tool with single data extraction. Gastrointestinal AEs were modelled using a Bayesian network meta-analysis (NMA), using fixed and random effects for each recommended dose (treatment-specific NMA) and class (drug-class NMA).ResultsTreatment-specific NMA included 17 trials (n = 9030; 3665 event-weeks). Nausea rates were significantly lower with iGlarLixi versus exenatide 10 μg twice daily (rate ratio: 0.32; 95% credible interval: 0.15, 0.66), once-daily lixisenatide 20 μg (0.35; 0.24, 0.50) and liraglutide 1.8 mg once daily (0.48; 0.23, 0.98). Rates were numerically, but not statistically, lower versus once-weekly semaglutide 1 mg (0.60; 0.30, 1.23) and dulaglutide 1.5 mg (0.60; 0.29, 1.26), and numerically, but not statistically, higher versus once-weekly exenatide (1.91; 0.91, 4.03). Sensitivity analysis results were similar. In a naïve, pooled analysis, vomiting was lower with iGlarLixi versus other GLP-1 RAs.ConclusionsDuring the first 12 weeks of treatment, iGlarLixi was generally associated with less nausea and vomiting than single-agent GLP-1 RAs. Enhanced gastrointestinal tolerability with fixed-ratio combinations may favour treatment persistence.
| S-EPMC7756611 | biostudies-literature
Project description:Glucagon-like peptide 1 (GLP-1) is a natural peptide agonist of the GLP-1 receptor (GLP-1R) found on pancreatic β-cells. Engagement of the receptor stimulates insulin release in a glucose-dependent fashion and increases β-cell mass, two ideal features for pharmacologic management of type 2 diabetes. Thus, intensive efforts have focused on developing GLP-1-based peptide agonists of GLP-1R for therapeutic application. A primary challenge has been the naturally short half-life of GLP-1 due to its rapid proteolytic degradation in vivo. Whereas mutagenesis and lipidation strategies have yielded clinical agents, we developed an alternative approach to preserving the structure and function of GLP-1 by all-hydrocarbon i, i + 7 stitching. This particular "stitch" is especially well-suited for reinforcing and protecting the structural fidelity of GLP-1. Lead constructs demonstrate striking proteolytic stability and potent biological activity in vivo. Thus, we report a facile approach to generating alternative GLP-1R agonists for glycemic control.
| S-EPMC7366314 | biostudies-literature
Project description:Co-agonists at the glucagon-like peptide-1/glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Unlike GLP1, glucagon directly acts on the liver to reduce fat content. To date most metabolic studies have looked at heavily GLP1R-biased co-agonists and have not distinguished weight-loss versus weight loss-independent effects. We demonstrate that 24 days’ treatment with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, in mice with hepatic steatosis secondary to diet-induced obesity leads to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice: some known targets of glucagon signalling and others with as yet unclear physiological significance. Our study supports the development of GLP1/GCGR co-agonists for treatment of MASLD and related conditions.
2024-06-11 | GSE243681 | GEO
Project description:Obesity remains a major public health problem, affecting almost half of adults in the United States. Increased risk of cardiovascular disease (CVD) and CVD mortality are major obesity-related complications, and management guidelines now recommend weight loss as a key strategy for the primary prevention of CVD in patients with overweight or obesity. The recently demonstrated efficacy of some pharmacologic therapies for chronic weight management may encourage health care professionals to recognize obesity as a treatable serious chronic disease and motivate patients to re-engage with weight loss when previous attempts have been ineffective or unsustainable. This review article summarizes the benefits and challenges associated with lifestyle changes, bariatric surgery, and historical pharmacologic interventions in the treatment of obesity, and focuses on the current evidence for the efficacy and safety of the newer glucagon-like peptide-1 receptor agonist medications in the management of obesity and potential reduction of CVD risk. We conclude that the available evidence demonstrates glucagon-like peptide-1 receptor agonists should be strongly considered in clinical practice for the treatment of obesity and reduction of CVD risk in people with type 2 diabetes. If ongoing research proves glucagon-like peptide-1 receptor agonists to be effective in reducing the risk of CVD onset in patients with obesity, irrespective of type 2 diabetes status, it will herald a new treatment paradigm in this setting, and now is the time for health care professionals to better recognize the benefits of these agents.
| S-EPMC10381974 | biostudies-literature
Project description:Data from randomized clinical trials with metabolic outcomes can be used to address concerns about potential issues of cardiovascular safety for newer drugs for type 2 diabetes. This meta-analysis was designed to assess cardiovascular safety of GLP-1 receptor agonists.MEDLINE, Embase, and Cochrane databases were searched for randomized trials of GLP-1 receptor agonists (versus placebo or other comparators) with a duration ?12 weeks, performed in type 2 diabetic patients. Mantel-Haenszel odds ratio with 95% confidence interval (MH-OR) was calculated for major cardiovascular events (MACE), on an intention-to-treat basis, excluding trials with zero events.Out of 36 trials, 20 reported at least one MACE. The MH-OR for all GLP-1 receptor agonists was 0.74 (0.50-1.08), P = .12 (0.85 (0.50-1.45), P = .55, and 0.69 (0.40-1.22), P = .20, for exenatide and liraglutide, resp.). Corresponding figures for placebo-controlled and active comparator studies were 0.46 (0.25-0.83), P = .009, and 1.05 (0.63-1.76), P = .84, respectively.To date, results of randomized trials do not suggest any detrimental effect of GLP-1 receptor agonists on cardiovascular events. Specifically designed longer-term trials are needed to verify the possibility of a beneficial effect.
| S-EPMC3092497 | biostudies-literature