Review
This narrative review synthesizes the current landscape of FDA-approved and investigational pharmacotherapies for obesity management. The authors examine six approved long-term agents — orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide, and tirzepatide — covering their mechanisms of action, pivotal efficacy data, safety profiles, indications, and prescribing considerations. The review notes that semaglutide and tirzepatide have substantially raised expectations for pharmacological weight loss compared to older agents. Emerging investigational compounds, including oral GLP-1 receptor agonists such as orforglipron and multireceptor agonists such as retatrutide, are highlighted as showing even greater early-phase efficacy signals. Common safety considerations discussed include gastrointestinal adverse effects, gallbladder events, pancreatitis risk, thyroid C-cell tumor warnings, teratogenicity, and cost and access barriers. The authors emphasize that patient selection should be guided by BMI, comorbidities, and contraindications. Key limitations acknowledged by the review include a lack of direct head-to-head comparative trials, limited long-term cardiovascular outcomes data, and questions about weight durability after treatment discontinuation. The authors identify these gaps as priorities for future research.
Review
This review paper surveys the current landscape of obesity pharmacotherapy, covering both approved and emerging treatment options. The authors outline the clinical burden of obesity, noting its associations with diabetes, cardiovascular disease, hypertension, and hyperlipidemia, and briefly describe non-pharmacological management strategies such as nutritional therapy and exercise. The review catalogues FDA-approved anti-obesity medications — orlistat, setmelanotide, phentermine-topiramate, naltrexone-bupropion, liraglutide, semaglutide, and tirzepatide — and highlights semaglutide as having a favorable clinical and regulatory profile. Emerging agents discussed include orforglipron, a non-peptide oral GLP-1 receptor agonist positioned as a potentially convenient alternative to injectable therapies. The authors also explore adjunctive approaches such as probiotics, prebiotics, fecal microbiota transplantation, and mitochondrial uncouplers. Key barriers to obesity management — including financial constraints, inadequate clinician training, and lack of reimbursement — are identified. The paper concludes by advocating for innovative, multidisciplinary, and patient-centered care models. As a narrative review, the paper does not generate new primary data, and conclusions reflect the authors' synthesis of existing literature rather than independent experimental findings.
Insufficient
SYNCHRONIZE™-2 is an ongoing double-blind, randomized, placebo-controlled Phase 3 trial evaluating survodutide — an investigational dual glucagon receptor/GLP-1 receptor agonist — for weight reduction in adults with obesity and type 2 diabetes (T2D). This paper reports only the baseline characteristics of the 752 enrolled participants across 133 sites in 19 countries; efficacy and safety results are not yet available. Participants were randomized 1:1:1 to one of two doses of weekly subcutaneous survodutide or placebo, alongside diet and physical activity guidance. At baseline, the cohort had a mean age of 55.7 years, mean BMI of 36.5 kg/m², mean body weight of 104.1 kg, and mean HbA1c of 7.4%; roughly half were female. Common comorbidities included hypertension (69%), dyslipidaemia (68%), and obstructive sleep apnoea (17%). The geographic distribution included participants from Europe, North America, and East Asia, suggesting reasonable diversity. Primary endpoints are percentage change in body weight and achievement of ≥5% weight loss at Week 76. A key limitation of this publication is that it presents only baseline data — no outcomes are yet reported — so no conclusions about efficacy or safety of survodutide can be drawn from this paper alone.
Diabetes, obesity & metabolism · Nov 2025DOI ↗ In vitro
This study investigated whether Tβ4-17, a small bioactive peptide derived from the precursor protein thymosin β4 and identified via iTRAQ technology, could enhance the sensitivity of cisplatin (DDP)-resistant ovarian cancer cells to chemotherapy. Using in vitro cell line models of DDP-resistant ovarian cancer, the researchers tested the combination of Tβ4-17 with DDP on cell proliferation, migration, and apoptosis. Results indicated that the combination significantly inhibited proliferation and migration of resistant cells while promoting apoptosis compared to either treatment alone. Mechanistically, the study found that NF-κB (specifically the p65 subunit) was highly expressed in DDP-resistant ovarian cancer cells, and that Tβ4-17 appeared to downregulate NF-κB p65 protein expression. These findings were supported by qRT-PCR, Western blot, CCK-8 assays, EDU fluorescence proliferation assays, and scratch migration assays, as well as experiments using NF-κB inhibitors and activators. Key limitations include reliance solely on in vitro cell line models with no animal or human data, and the absence of pharmacokinetic or safety assessments. The study suggests a potential mechanism by which Tβ4-17 may overcome chemoresistance in ovarian cancer but requires substantial further validation.
Medical oncology (Northwood, London, England) · Nov 2025DOI ↗ Insufficient
This paper presents a hypothesis-generating perspective piece examining the potential interaction between amylin-based therapies — including the pramlintide and cagrilintide receptor agonists, and the combination therapy CagriSema — and the renin-angiotensin system (RAS). The authors hypothesize that amylin receptor agonists may activate the RAS, which could potentially counteract the cardiorenal benefits of these obesity and type 2 diabetes treatments. However, they note the paradox that CagriSema demonstrated meaningful blood pressure reductions in phase 3 trials. The authors further hypothesize that concurrent use of RAS inhibitors (ACE inhibitors or angiotensin-receptor blockers) may redirect amylin-induced RAS activation toward the protective "alternative RAS pathway," promoting vasodilatory, anti-inflammatory, and antiproliferative effects via Mas receptors. To test these hypotheses, the authors propose a research agenda encompassing preclinical studies, post-hoc trial analyses stratified by RAS inhibitor use, biomarker studies, and prospective mechanistic human studies. No original experimental data are presented. Key limitations include the entirely speculative nature of the central claims, the absence of direct supporting evidence, and reliance on inference from existing trial-level observations.
Lancet (London, England) · Nov 2025DOI ↗ Moderate · human
This systematic review, following PRISMA 2020 guidelines, examined the frequency, severity, and types of gastrointestinal (GI) adverse effects associated with anti-obesity medications in non-diabetic adults with obesity. Researchers searched PubMed, Google Scholar, BMJ, and Web of Science through July 2025, ultimately including 12 studies from 733 screened articles. The evidence base included one large cohort of 18,386 participants alongside smaller randomized and observational trials. The review found that nausea, vomiting, diarrhea, and constipation were the most frequently reported GI symptoms, occurring predominantly with GLP-1 receptor agonists such as semaglutide and tirzepatide, particularly during dose escalation phases. Orlistat was commonly associated with steatorrhea and flatulence, while phentermine was linked to reduced GI motility. Newer investigational agents, including retatrutide and orforglipron, also demonstrated notable GI side effect profiles. Natural products and other investigational agents reported fewer adverse events but lacked long-term data and standardized reporting. Key limitations include heterogeneity in study designs and inconsistent GI outcome reporting across included studies. The authors concluded that GI side effects are common but generally mild to moderate, and that standardized reporting and proactive clinical management strategies may improve patient adherence and tolerability.
Medicina (Kaunas, Lithuania) · Nov 2025DOI ↗ Insufficient
This paper reports the baseline characteristics of participants enrolled in SYNCHRONIZE-1, a multinational, randomized, double-blind, placebo-controlled Phase 3 trial evaluating survodutide — a dual glucagon receptor and GLP-1 receptor agonist — for weight management in adults with obesity but without type 2 diabetes. A total of 725 participants from 14 countries were randomized 1:1:1 to receive once-weekly subcutaneous injections of survodutide (up-titrated to 3.6 mg or 6.0 mg) or placebo over 76 weeks. At baseline, participants had a mean age of 47.1 years, mean BMI of 37.9 kg/m², and mean waist circumference of 115.2 cm; 59.4% were female. Common obesity-related complications included hypertension (40.0%), dyslipidaemia (33.7%), and prediabetes (30.2%). The primary endpoints are percent body weight change and achievement of ≥5% body weight reduction from baseline to Week 76. As this publication covers only baseline data, no efficacy or safety outcomes are yet reported. The study's key limitation at this stage is that it describes enrollment characteristics only, with no outcome data available.
Diabetes, obesity & metabolism · Nov 2025DOI ↗ Limited · human
This multicenter retrospective observational study used the TriNetX database (2018–2021) to examine whether adding a GLP-1 receptor agonist (GLP-1 RA) to an SGLT2 inhibitor (SGLT2i) provides additional benefit over SGLT2i monotherapy in adults with both heart failure (HF) and type 2 diabetes (T2D). From nearly 929,000 eligible patients, 25,989 received combination therapy and 54,619 received SGLT2i monotherapy; after propensity score matching, each group contained 23,240 patients. Over one year, the study found that the combination group had a significantly lower rate of all-cause death (2.8% vs. 6.3%) and hospitalization compared with the monotherapy group. While propensity score matching was used to balance baseline characteristics, the retrospective and observational design limits causal inference, as unmeasured confounders (e.g., prescribing patterns, disease severity, medication adherence) may have influenced outcomes. The TriNetX database also relies on real-world electronic health records, which can have coding inaccuracies. The authors conclude that combination SGLT2i and GLP-1 RA therapy was associated with lower all-cause mortality and hospitalization risk in this HF and T2D population, but prospective randomized trials are needed to confirm these findings.
BMJ open diabetes research & care · Nov 2025DOI ↗ Review
This review examines the role of glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) in kidney protection among people living with type 2 diabetes and obesity. The authors trace the evolution of GLP-1 research from its original characterization as a metabolic hormone—regulating insulin secretion, suppressing glucagon, and reducing insulin resistance partly through weight loss—toward a broader understanding of its effects on kidney physiology and clinical outcomes. The review summarizes preclinical data alongside landmark clinical trial findings, noting that renoprotective effects have been observed despite only modest GLP-1 receptor expression in the kidney. Key clinical outcomes discussed include changes in albuminuria, estimated glomerular filtration rate decline, and cardiovascular-renal endpoints drawn from large outcomes trials. The authors frame GLP-1 RAs as an area of intensive ongoing investigation for chronic kidney disease management in the relevant patient population. As a narrative review, this paper does not conduct original data collection or meta-analysis, and conclusions are therefore subject to the selection and interpretation choices of the authors. It provides a useful synthesis of the existing evidence base but does not itself constitute primary clinical trial data.
The Journal of clinical investigation · Nov 2025DOI ↗ Review
This review examines the relationship between glucagon-like peptide-1 (GLP-1) receptor agonists — a class of drugs used to treat obesity and type 2 diabetes — and cancer risk. The authors note that obesity and type 2 diabetes are established risk factors for several cancers, and that GLP-1 receptor agonists have become transformative treatments for these conditions. The review synthesizes current clinical evidence across multiple cancer types, including thyroid, pancreatic, gastrointestinal, and hormone-dependent malignancies. The authors report that recent meta-analyses generally do not support an increased cancer incidence with GLP-1 receptor agonist use, and suggest a potential risk-lowering effect in some cancer types. Preclinical studies are also discussed, with findings pointing to possible anticancer mechanisms even in non-obese models, including immune-modulating effects that may reflect direct action on immune cells or stem from improved metabolic function. The review highlights ongoing clinical trials and identifies key gaps in translational research, including questions about treatment timing, duration, concurrent anticancer therapies, and the distinction between cancer risk versus progression models. As a narrative review, it does not generate new primary data, and conclusions depend on the quality of the underlying studies reviewed.
The Journal of clinical investigation · Nov 2025DOI ↗ Preclinical
This study investigated the role of mast cell (MC)-derived thymosin β4 (Tβ4) in stress-induced intestinal barrier dysfunction in irritable bowel syndrome (IBS). Researchers measured Tβ4 levels in colonic mucus of IBS patients and used a combination of in vitro experiments, rodent models (including Tβ4-knockout rats and MC-deficient mice), and reconstitution experiments to examine mechanisms. The study found that Tβ4 levels were elevated in the colonic mucosa and intestinal MCs of IBS patients. In animal models, Tβ4 appeared to reduce tight junction proteins and the IL22RA1/Reg3γ cascade while increasing myosin light chain kinase activity, collectively impairing the epithelial barrier. Tβ4-deficient rats showed resistance to stress-induced barrier disruption, and reintroduction of Tβ4 or wild-type peritoneal MCs restored that disruption. Mechanistically, Tβ4 release from MCs was found to depend on corticotropin-releasing hormone receptor 1 signaling rather than classic degranulation, and its barrier-impairing effects were linked to inhibition of the IL22RA1/JAK1/STAT3 signaling pathway. Limitations include reliance on rodent models for mechanistic work, modest human clinical data, and the complexity of translating these findings to therapeutic applications.
World journal of gastroenterology · Nov 2025DOI ↗ Limited · human
This study used synthetic target trial emulation and computational predictive modeling to compare amylin-pathway therapies — specifically CagriSema, cagrilintide, and amycretin formulations — for obesity and type 2 diabetes. Following PRISMA 2020 and TARGET framework guidelines, the researchers pooled data from seven randomized controlled trials (N = 5,786 participants) published through September 2025. Rather than analyzing real individual patient data, they reconstructed high-precision synthetic individual patient datasets and applied network meta-analysis, dose-response modeling, virtual head-to-head comparisons, and machine learning. The study reported that synthetic data reconstruction achieved greater than 99% fidelity to source trials, and virtual modeling suggested CagriSema outperformed subcutaneous amycretin at matched timepoints (posterior probability >0.95). Dose-response modeling identified an estimated ED80 for amycretin and benefit-risk analysis suggested a potential therapeutic window in the 10–20 mg subcutaneous range. Machine learning models predicted treatment response with 82–87% accuracy from baseline characteristics. Key limitations include reliance on reconstructed — not real — individual patient data, indirect comparisons rather than direct head-to-head trial evidence, and calibration metrics indicating moderate model uncertainty. The authors suggest these findings may inform future confirmatory trial design.
Metabolism open · Oct 2025DOI ↗ Strong · human
This systematic review and network meta-analysis examined the renal effects of three classes of novel antidiabetic agents—DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors—in adults with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Researchers searched four major databases through July 2025 and identified 20 randomized controlled trials enrolling 80,670 participants, with a minimum follow-up of 24 weeks. Key outcomes assessed were composite renal outcomes, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR). The study found that several agents significantly reduced composite renal outcomes compared with placebo; dapagliflozin demonstrated the largest effect (high-certainty evidence), followed by canagliflozin, empagliflozin, and select GLP-1 agonists (efpeglenatide, sotagliflozin, semaglutide, dulaglutide). Canagliflozin most strongly reduced UACR, while dapagliflozin showed no significant effect on this measure. No agent significantly altered eGFR. DPP-4 inhibitors showed no renal benefit. Certainty of evidence, assessed via GRADE, was high for direct placebo-controlled comparisons but fell to low or very low for indirect network estimates. A key limitation is that conclusions about head-to-head drug comparisons rely on indirect evidence, which carries greater uncertainty.
Diabetes, obesity & metabolism · Oct 2025DOI ↗ Animal only
This study describes the development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method for measuring tirzepatide — a dual GIP/GLP-1 receptor agonist — in rat plasma. Researchers used protein precipitation with methanol for sample preparation, a peptide C18 column for chromatographic separation, and positive electrospray ionization with multiple reaction monitoring for detection, using semaglutide as an internal standard. The method demonstrated good linearity (1–1000 ng/mL), with intra- and inter-day accuracy and precision meeting regulatory criteria. Stability under various storage and handling conditions was also confirmed. The validated method was then applied to a pharmacokinetic study in rats administered tirzepatide intravenously and subcutaneously at 0.3 mg/kg. The study reports terminal half-lives of approximately 10 hours via both routes and estimates subcutaneous bioavailability at roughly 62%. Key limitations include the exclusive use of a rat model, a single dose level, and a small number of animals typical of preclinical PK studies, meaning findings may not translate directly to humans. The authors suggest the method could be adapted for quantifying other structurally similar peptide therapeutics.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences · Oct 2025DOI ↗ Review
This narrative review examines pharmacologic management of vasomotor symptoms (VMS) and decreased libido in breast cancer patients receiving endocrine therapy — a population that commonly experiences new or worsened menopausal symptoms. The authors searched PubMed, Cochrane Library, and Web of Science to summarize established agents (SSRIs, SNRIs, gabapentin, clonidine) and highlight emerging therapies: fezolinetant and elinzanetant (neurokinin 3 receptor antagonists for VMS), and flibanserin and bremelanotide (serotonin/dopaminergic modulator and melanocortin receptor agonist, respectively, for low libido). The review notes that existing options provide inadequate symptom relief, representing a meaningful therapeutic gap. Crucially, the authors emphasize that clinical trials supporting these novel agents explicitly excluded breast cancer patients, meaning their safety and efficacy in this population remain unestablished. The paper aims to equip clinicians with practical considerations for weighing these therapies in breast cancer patients while awaiting dedicated research. Key limitations include the review format, reliance on trials conducted in the general population, and the absence of breast cancer-specific clinical data for the highlighted novel agents.
Expert review of clinical pharmacology · Oct 2025DOI ↗ Moderate · humanPreprint
This meta-analysis pooled data from four randomized controlled trials (n = 918) to evaluate the efficacy of mazdutide — a dual GLP-1 and glucagon receptor agonist — in nondiabetic adults with overweight or obesity. Researchers searched PubMed, Scopus, and Web of Science and applied a random-effects model to analyze primary outcomes including body weight, BMI, and waist circumference, along with secondary cardiometabolic markers. The pooled analysis found that, compared with placebo, mazdutide was associated with statistically significant reductions in body weight (mean difference: −7.72 kg), BMI (−2.84 units), waist circumference (−5.76 cm), HbA1c (−0.30%), LDL cholesterol (−10.59 mg/dL), total cholesterol (−18.61 mg/dL), and triglycerides (−49.87 mg/dL). The authors concluded that mazdutide shows promise as a pharmacotherapy option for this population. Key limitations include the small number of included trials (n = 4), the relatively modest total sample size, the lack of long-term follow-up data, and the preprint status of this analysis, meaning it has not yet undergone formal peer review. Findings should therefore be interpreted with caution pending publication.
Unknown journal · Oct 2025DOI ↗ Review
This review paper examines the potential role of nutrient-stimulated hormone-based therapies (NuSHs) — particularly GLP-1 receptor agonists — in the prevention and management of metabolic dysfunction-associated steatohepatitis (MASH)-related hepatocellular carcinoma (HCC). The authors contextualize MASH as the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), which is now the most prevalent chronic liver disease in Western populations. The review synthesizes emerging clinical and preclinical evidence suggesting that NuSHs can resolve MASH without worsening fibrosis, primarily through weight loss and improved insulin sensitivity. However, the authors note that benefits appear less pronounced in cirrhotic patients, implying greater utility in early disease stages. Preclinical models suggest NuSHs may reduce MASH-related HCC incidence and tumor burden through systemic metabolic improvements rather than direct anti-cancer mechanisms. Observational data from bariatric surgery populations further support a preventive role for weight loss. The authors also propose that integrating NuSHs into post-locoregional HCC treatment pathways could delay systemic therapy, improve immunotherapy synergy, and enhance transplant eligibility. Key limitations include the indirect nature of evidence, inconsistent fibrosis regression data, and an absence of trials with oncological primary endpoints.
Journal of clinical and translational hepatology · Oct 2025DOI ↗ Insufficient
This study focused on the development and validation of an analytical detection method — not a clinical intervention — for identifying growth hormone-releasing hormone (GHRH) and its synthetic analogs (sermorelin/CJC-1293, tesamorelin, and CJC-1295) in human urine samples for anti-doping purposes. These peptides are banned by the World Anti-Doping Agency (WADA) due to their potential performance-enhancing effects. The researchers developed a nano liquid chromatography coupled with quadrupole/orbitrap mass spectrometry (nano-LC-Q/Orbitrap MS) approach, systematically optimizing sample preparation steps including solid-phase extraction (SPE) and ultrafiltration. The finalized workflow — ultrafiltration followed by SPE — was fully validated per WADA guidelines, assessing selectivity, reliability, limits of detection (LOD ≤ 0.5 ng/mL), limits of identification (LOI 0.5–0.75 ng/mL), carryover, robustness, autosampler stability, and matrix effects. The method demonstrated sufficient sensitivity for both screening and confirmation of target peptides in urine. A key limitation is that this is a purely analytical/methodological study; it provides no clinical, pharmacological, or physiological data about the effects of these peptides in humans, and its findings are confined to laboratory detection performance.
Journal of pharmaceutical and biomedical analysis · Oct 2025DOI ↗ Animal only
This study investigated the role of ferroptosis (a form of iron-dependent regulated cell death) in pulpitis and evaluated whether thymosin α1 (Tα1) could mitigate this process. Using single-cell RNA sequencing (scRNA-seq) of tissue from 3 pulpitis and 3 healthy pulp samples, researchers identified 12 distinct cell clusters and found that differentially expressed ferroptosis-related genes (DE-FRGs) were broadly present across clusters in pulpitis tissue. Elevated reactive oxygen species (ROS) and Fe²⁺ levels, alongside reduced GPX4 and elevated PTGS2 expression by immunohistochemistry, suggested active ferroptosis in inflamed pulp. In LPS-stimulated dental pulp cells (DPCs) in vitro, Tα1 treatment was associated with increased GPX4 and FTL expression and reduced inflammatory markers (TNF-α, IL-1β, IL-6) and Fe²⁺ levels. In rat pulpitis models, delivery of prothymosin α (PTMA, the Tα1 precursor) via gelatin sponge or direct injection reduced inflammatory cell infiltration, decreased PTGS2, and increased GPX4. RNA sequencing of LPS-stimulated DPCs confirmed reversal of DE-FRG expression with Tα1 treatment. Key limitations include small human tissue sample sizes (n=3 per group), reliance on animal and cell models for intervention data, and the lack of human clinical trials.
International journal of oral science · Oct 2025DOI ↗ In vitro
This study investigated PapB, a radical S-adenosyl-l-methionine (rSAM) enzyme involved in the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs). Classically, RiPP maturase enzymes require an N-terminal leader sequence on the precursor peptide to guide substrate recognition and modification. The researchers discovered that PapB can function in a "leader-independent" manner — meaning it can process peptide substrates that entirely lack canonical leader sequences. To demonstrate the practical utility of this finding, the team applied PapB to three analogues of glucagon-like peptide (GLP-1) pathway agonists — a therapeutically relevant class of peptides — and showed that the enzyme achieved complete conversion of each linear peptide into a thioether-macrocyclized (C-terminally cyclized) product. The study is primarily a biochemical and enzymological characterization conducted in vitro, with no human or animal subjects involved. Limitations include that all work was performed outside of a biological system, and the therapeutic relevance of the resulting macrocyclic GLP-1 analogues in vivo remains to be established. The findings position PapB as a potentially versatile biocatalytic tool for generating conformationally constrained peptide drug candidates.
ACS bio & med chem Au · Oct 2025DOI ↗