GLP-1RA类单靶点和双靶点药物减重与GIAE的相关性及亚组差异

To evaluate gastrointestinal adverse events (AEs) and the impact of nausea, vomiting or diarrhoea (N/V/D) and any gastrointestinal (GI) AEs overall on weight change with tirzepatide across the SURPASS‐1 to ‐5 clinical trials.

BACKGROUND A knowledge gap remains in how the rate of body weight reduction impacts efficacy and safety of obesity management medications. This SURMOUNT-5 post hoc analysis aimed to define rapid responders and evaluated efficacy and safety of tirzepatide vs. semaglutide in rapid responders vs non-rapid responders. METHODS Rapid responders and non-rapid responders were defined as participants that obtained ≥15% and <15% body weight reduction by Week 24, respectively. Baseline characteristics, and proportion of participants achieving body weight reduction thresholds by Week 72 were assessed. End-of-study safety and gastrointestinal adverse events measures were summarized. RESULTS Overall, 32.3% were rapid responders (tirzepatide: 44%, semaglutide: 21%). The proportions of participants achieving body weight reduction thresholds by Week 72 were higher for rapid responders vs non-rapid responders. Safety trends for tirzepatide and semaglutide were similar between responder groups. A numerically higher number of gastrointestinal/hepatobiliary adverse events were reported in rapid responders. Study treatment completion was similar among rapid responders and non-rapid responders for both treatments. CONCLUSIONS In this post hoc analysis of SURMOUNT-5, a greater proportion of tirzepatide-treated participants in both responder groups achieved all body weight reduction thresholds vs semaglutide. Although rapid responders experienced more gastrointestinal/hepatobiliary adverse events in both treatments, this did not affect rates of study treatment completion relative to non-rapid responders. TRIAL REGISTRATION clinicaltrials.gov identifier NCT05822830.

… -like peptide 1 (GIP/GLP-1) receptor agonist (GIP/GLP-1 RA), … contributes to chronic weight management and glycaemia … GI event, and B, Proportion of participants with each GI event. …

Key Points Question How does weight loss differ between patients receiving tirzepatide compared with semaglutide among a clinical population of adults with overweight or obesity? Findings In this cohort study of 18 386 propensity-score matched patients initiating tirzepatide or semaglutide labeled for type 2 diabetes, discontinuation was common; most achieved weight loss of 5% or greater within 1 year of treatment. Meaning Although most adults with overweight or obesity experienced 5% or greater weight loss with treatment, the benefit was greater with tirzepatide.

Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GLP-1/GIP receptor agonists are highly effective agents for the treatment of type 2 diabetes and obesity. However, gastrointestinal (GI) adverse events remain the most common limitations to long-term therapy. Methods A narrative review with a structured literature search was conducted using PubMed, Embase, and Cochrane Library databases from inception to March 2025. Randomized controlled trials, observational studies, meta-analyses, and pharmacovigilance reports evaluating GI adverse effects of GLP-1–based therapies were included. Results Nausea, vomiting, diarrhea, and constipation were the most frequently reported GI adverse events, generally dose-dependent and transient. Delayed gastric emptying, gastroparesis-like symptoms, intestinal obstruction, biliary disease, and pancreatic safety concerns were variably reported, with heterogeneous and sometimes conflicting evidence across studies. Conclusion GLP-1–based therapies are associated with predictable GI adverse effects, most of which are mild to moderate and manageable. Serious complications appear rare, but evidence remains inconsistent. Individualized risk assessment, patient education, and careful dose titration are essential for optimizing long-term tolerability.

Glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic peptide receptor (GIPR) agonistic analogs have yielded superior results in enhancing glycemic control and weight management compared to GLP-1R agonism alone. Intriguingly, GIPR agonism appears to induce antiemetic effects, potentially alleviating part of the nausea and vomiting side effects common to GLP-1R agonists like semaglutide. Here, we show in rats and shrews that GIPR agonism blocks emesis and attenuates other malaise behaviors elicited by GLP-1R activation while maintaining reduced food intake and body weight loss and improved glucose tolerance. The GLP-1R/GIPR agonist tirzepatide induced significantly fewer side effects than equipotent doses of semaglutide. These findings underscore the therapeutic potential of combined pharmaceutical strategies activating both incretin systems, leading to enhanced therapeutic index and reduced occurrence of nausea and vomiting for obesity and diabetes treatments.

… The overall risk of gastrointestinal adverse events was 86% in GLP- 1 group vs. … weight management, including mitigating the side effects. In summary, both semaglutide and tirzepatide …

… enhancing glycemic control, facilitating weight reduction, and … adoption of Semaglutide and Tirzepatide-including their … and vomiting, with GI adverse events being the leading cause of …

Tirzepatide has positive effects on weight loss in individuals with overweight or obesity. Considering its broad side‐effect profile, its efficacy and safety in individuals without diabetes mellitus (DM) are yet to be fully understood. To address this, we conducted a comprehensive meta‐analysis of six randomized trials on individuals with overweight or obesity, without DM, which showed that tirzepatide, when compared with placebo, resulted in a change in percentage body weight with a mean difference (MD) of −16.32% (95% CI: −18.35 to −14.29) and change in absolute body weight in kilograms (MD −13.95 kg; −18.83 to −9.07). There were significant reductions in body mass index and waist circumference when compared with placebo, with MDs of −5.89 kg/m2 (−8.97 to −2.81) and −12.31 cm (−13.93 to −10.68), respectively. It was associated with gastrointestinal (GI) side effects: nausea (relative risk [RR] 3.11; 2.74–3.54), vomiting (RR 5.94; 4.50–7.85), diarrhea (RR 2.92; 2.53–3.37), and constipation (RR 2.85; 2.38–3.42). Serious adverse events were not statistically significant (RR 0.93; 0.76–1.13), but serious GI events and discontinuation due to adverse events were significant (RRs 3.07; 2.03–4.66, and 2.29; 1.74–3.01, respectively). In conclusion, this meta‐analysis suggests that in patients with overweight or obesity without DM, tirzepatide is effective for significant weight loss. Though the overall risk of serious adverse events is not higher compared with placebo, it carries an elevated risk of GI side effects, serious GI events, and discontinuation due to adverse effects.

Background With the increasing clinical use of tirzepatide, its safety profile has garnered significant attention. This article systematically reviews case reports of tirzepatide-associated adverse drug reactions (ADRs) to summarize their characteristics. Method We searched PubMed, Web of Science, ScienceDirect, Wiley Online, and Embase databases for case reports on tirzepatide adverse events using the keywords: “tirzepatide”, “adverse reaction”, “adverse event”, “side effect”, “safety”, “case report”, “induced”, “associated”, and “related”. Statistical analysis was performed on the identified cases. Results A total of 43 cases of tirzepatide ADR were identified from 37 articles. Among these patients (24 female, 19 male; mean age 50.23 ± 17.24 years), 19 involved concomitant medications affecting multiple systems. ADR was reported in each dosage of tirzepatide, with the most occurring at 2.5–5 mg (16 cases), and primarily occurred within 1–6 months of initiation. Regarding rechallenge, 15 patients discontinued tirzepatide, three continued use, and one reduced the dose. ADR involved seven gastrointestinal tract and endocrine systems, including liver and gallbladder, circulation, nerve, skin, and urinary. Notable manifestations included ketoacidosis, liver injury, hypotension, intestinal obstruction, and allergic reactions. Among them, ketoacidosis and common peroneal neuropathy causing foot sagging, acute appendicitis, lower limb venous thrombosis, gastric outlet obstruction, gastric emptying delay, and acute liver injury were not mentioned in the drug instructions. ADR correlation assessment was performed for 8 patients:4 cases of cardiovascular events and ketoacidosis were all evaluated as “probable” using the Naranjo scale, 3 cases of liver injury were assessed by RUCAM (2 case as “possible”, 1 cases as “probable”), 1 case did not specify the evaluation method, with the result being “highly probable”. All 43 patients underwent ADR correlation re-evaluation:32 cases (74.42%) were assessed as “probable”,11 cases (25.58%) were assessed as “possible”. Conclusion Tirzepatide-associated ADRs most commonly occur within the first 6 months of treatment, primarily affecting the digestive, endocrine, liver, and gallbladder systems. Enhanced monitoring of liver and kidney function is warranted, especially in patients concurrently taking other potentially hepatotoxic or nephrotoxic medications. Additionally, intensified therapeutic drug monitoring is recommended for patients with cardiovascular disease, those requiring weight-based dosing adjustments, and those experiencing rapid weight loss.

Agonists targeting the receptors of incretin hormones, glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, have been well established for the treatment of type 2 diabetes mellitus. There is increasing awareness that gastroenterologists and hepatologists should be treating obesity when patients present to their clinics. In addition, gastroenterologists and hepatologists should be aware of the effects of these classes of medications prescribed by other providers. Therefore, given the widespread use of incretin agonists for obesity treatment and weight loss, it is important to recognize their effects in the gastrointestinal tract, which could constitute significant benefits in weight loss and cardiometabolic benefits, but can be associated with adverse effects that constitute a potential barrier to their use, particularly at higher doses. Multiple studies reviewed in this article document the diverse effects of these drugs on the GLP-1 receptors that are widely expressed in the human body, including the nervous system modulating appetite, the gastrointestinal tract modifying gastric emptying, and lipid metabolism regulation leading to reduction in fat deposition. The objective of this review is to summarize the mechanism of action of incretin receptor agonists, their effects in the gastrointestinal tract, and implications in clinical practice, particularly in the practice of gastroenterology, endoscopy, and surgery.

The availability of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) such as liraglutide and semaglutide, and a GLP-1 and glucose dependent insulinotropic polypeptide coagonist (tirzepatide) represents a paradigm shift in the management of both type 2 diabetes and obesity. There is now considerable attention, including in the public media, on the effect of both long-acting and short-acting GLP-1RAs to delay gastric emptying. Although slowed gastric emptying is integral to reducing post-prandial blood glucose responses in type 2 diabetes, marked slowing of gastric emptying might also increase the propensity for longer intragastric retention of food, with a consequent increased risk of aspiration at the time of surgery or upper gastrointestinal endoscopy. This Personal View summarises current knowledge of the effects of GLP-1 and GLP-1RAs on gastrointestinal physiology, particularly gastric emptying, and discusses the implications for the development of sound pre-operative or pre-procedural guidelines. The development of pre-procedural guidelines is currently compromised by the poor evidence base, particularly in relation to the effect of long-acting GLP-1RAs on gastric emptying. We suggest pre-procedural management pathways for individuals on GLP-1RA-based therapy and discuss priorities for future research.

Delayed gastric emptying (GE) is a well-known effect of glucagonlike peptide-1 (GLP-1). Similarly, glucagon (GCG) has been shown to slow GE in rodents and humans, while glucosedependent insulinotropic polypeptide (GIP) does not appear to impact GE. Retatrutide (LY3437943) is a novel GIP/GLP-1/GCG receptor agonist (RA) under investigation for chronic weight management and its complications. It is more potent at the human GIP receptor and less potent at GCG and GLP-1 receptors versus the native hormones, with a half-life of approximately 6 days supporting onceweekly dosing. In adults with type 2 diabetes, retatrutide reduced glycated hemoglobin (HbA1c) and body weight versus placebo and dulaglutide 1.5 mg after 12 weeks of treatment, with mild or moderate gastrointestinal events being the most common treatmentemergent adverse events. GE is a major determinant of glycemic response after food intake. Delayed GE may reduce food intake and subsequently impact weight loss. While GLP-1 RAs and the GIP/GLP-1 RA tirzepatide transiently delay GE, the effects of retatrutide are unknown. We investigated the effect of retatrutide versus selective GLP-1 RAs on GE in non-clinical and clinical studies. 2 | METHODS

ABSTRACT Background Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and dual GIP/GLP‐1 RAs are widely used to manage obesity, prediabetes and type 2 diabetes, typically in combination with lifestyle interventions. Their nutritional implications, however, remain unclear. This systematic review summarised evidence from randomised clinical trials investigating dietary strategies and nutritional management in individuals treated with these medications. Methods The review followed PRISMA guidelines and was registered in PROSPERO (CRD420251181076). Searches were conducted in PubMed, Embase, Scopus and Web of Science. Eligible studies were randomised clinical trials evaluating adults receiving GLP‐1 or dual GIP/GLP‐1 agonists in conjunction with lifestyle or dietary guidance. Outcomes included gastrointestinal symptoms, muscle and bone health and nutritional adequacy. Results Sixteen trials involving 7096 participants were included. GLP‐1 and dual agonists consistently increased gastrointestinal symptoms such as nausea, diarrhoea, constipation and vomiting. These effects were often dose‐related and occurred despite background lifestyle or dietary interventions. Lean mass was generally preserved, with reductions proportional to overall weight loss. No study directly assessed bone health, and none reported clinically relevant nutritional deficiencies. Most trials presented a low risk of bias. Conclusion GLP‐1 and dual GIP/GLP‐1 agonists frequently cause gastrointestinal discomfort but tend to preserve lean mass during weight loss when used alongside lifestyle interventions. Although dietary guidance is commonly provided, evidence on optimal nutritional approaches remains limited. Further trials are needed to clarify protein requirements, assess musculoskeletal outcomes and establish evidence‐based dietary recommendations to support combined treatment strategies.

Background: Till date, there is no Cochrane meta-analysis available which has analyzed efficacy and safety of tirzepatide in type-2 diabetes. This meta-analysis was undertaken to address this knowledge gap. Methods: Electronic databases were searched for randomized controlled trials (RCTs) involving people with diabetes receiving tirzepatide compared to a placebo/active comparator. Primary outcome was to evaluate changes in HbA1c. Secondary outcomes were to evaluate alterations in blood–glucose, glycemic targets, weight, lipids, and adverse events. Results: From 34 articles initially screened, data from six RCTs involving 3484 patients were analyzed. Over 12–52 weeks, individuals receiving tirzepatide had significantly greater lowering of HbA1c [mean difference (MD) = -0.75% (95% confidence interval (CI): -1.05 to -0.45); P < 0.01; I2 = 100%], fasting glucose [MD = -0.75 mmol/L (95% CI: -1.05 to– -0.45); P < 0.01; I 2 = 100%], 2-h post-prandial-glucose [MD = -0.87 mmol/L (95% CI: -1.12 to -0.61); P < 0.01; I2 = 99%], weight [MD = -8.63 kg (95% CI: -12.89 to -4.36); P < 0.01; I2 = 100%], body mass index [MD = -1.80 kg/m2 (95% CI: -2.39 to -1.21); P < 0.01; I2 = 99%], and waist circumference [MD = -4.43 cm (95% CI: -5.31 to -3.55); P < 0.01; I2 = 95%] as compared to dulaglutide, semaglutide, degludec, or glargine. Patients receiving tirzepatide had higher odds of achieving HbA1c <6.5% compared to active controls [odds ratio (OR) = 4.39 (95% CI: 2.44–7.92); P < 0.01; I2 = 90%]. Tirzepatide use had significantly higher odds of weight loss >5% [OR = 19.18 (95% CI: 2.34–157.17); P < 0.01; I2 = 99%], >10% [OR = 21.40 (95% CI: 2.36–193.94); P < 0.01; I2 = 98%], and >15% [OR = 32.84 (95% CI: 2.27–474.33); P = 0.01; I2 = 96%] compared to active-control group. Treatment-emergent adverse events [risk ratio (RR) = 1.43 (95% CI: 1.14–1.80); P < 0.01; I2 = 40%] and severe adverse events [RR = 1.00 (95% CI: 0.64–1.57); P = 1.00; I2 = 49%] were not different. High data heterogeneity and the presence of publication bias limits the grading of current data from “moderate to low.” Conclusion: Tirzepatide has impressive glycemic efficacy and weight-loss data over 1-year clinical use. The need for higher grade, long-term efficacy, and safety data remains.

Glucagon-like peptide-1 (GLP-1) receptor agonists are incretin analogues that promote glucose-mediated insulin release and are used to treat type 2 diabetes mellitus and obesity. GLP-1 receptor agonists and GLP-1 and glucose-dependent insulinotropic peptide agonists have several mechanisms of action, including reduction of gastric emptying, inhibition of glucagon secretion, beneficial changes in the intestinal microbiome, and direct effects on hypothalamic nuclei to enhance satiety (which promotes weight loss). Beyond the impressive effects of GLP-1 receptor agonists on blood glucose levels and body weight, large-scale randomized, controlled trials have shown that GLP-1 receptor agonists reduce cardiovascular risk and slow progression to renal failure in persons at high risk and those with type 2 diabetes. Adverse side effects from GLP-1 receptor agonists are mostly gastrointestinal but may also include loss of muscle and bone mass. Questions remain about long-term adherence, weight regain after discontinuation of treatment, and the functional implications of the loss of muscle and bone mass. Recent and ongoing targeted studies suggest the possibility of additional uses for GLP-1 receptor agonists.