Moderate · humanPreprint
This systematic review and meta-analysis (PROSPERO-registered) pooled data from four randomized controlled trials (n = 4,810 adults with overweight or obesity) to compare the fixed-dose combination of cagrilintide and semaglutide (CagriSema) against semaglutide alone, cagrilintide alone, or placebo. The authors found that, across all comparators, CagriSema was associated with statistically greater percent body weight reduction: approximately 7.4 percentage points more than semaglutide, 8.8 percentage points more than cagrilintide, and 13.9 percentage points more than placebo. The likelihood of achieving ≥15% or ≥20% weight loss was reported to be 2–3 times higher with the combination. Waist circumference was also significantly reduced with CagriSema versus placebo (mean difference approximately −10.9 cm). No consistent differences in HbA1c were observed across comparisons. Gastrointestinal adverse events were more frequent with CagriSema, and treatment discontinuation rates were correspondingly higher in the combination group. Limitations include the small number of included trials (four), preprint status introducing risk of non-peer-reviewed data, and potential heterogeneity across trial designs and populations.
Unknown journal · Nov 2025DOI ↗ 🧪 TrialInsufficient
Registered N/A interventional trial (completed). Obesity is a chronic condition linked to numerous health risks and affects more than one billion people worldwide. While pharmacological treatments such as incretin-based therapies are available, they may have side effects, are not suitable for all patients, and adherence can be limited. Dietary supplements that influence appetite and satiety may represent an alternative or complementary approach. This study will evaluate whether a dietary supplement containing plant extracts stimulates the intestinal incretin response. The primary focus is the
ClinicalTrials.gov · Nov 2025View trial ↗ Limited · human
This retrospective, single-arm study evaluated the effects of a 7-day loading dose of thymosin α1 (Tα1) on peripheral blood lymphocyte counts, as well as the safety and efficacy of combining Tα1 with hypofractionated radiotherapy and PD-1 inhibitors in 48 patients with advanced or refractory cancers. Peripheral blood T cells, B cells, and natural killer cells were measured by flow cytometry before and after Tα1 administration. The study found that the 7-day Tα1 course was associated with statistically significant increases in total T cells, CD4+ T cells, and CD8+ T cells. Secondary outcomes including objective response rate, disease control rate, progression-free survival, and overall survival were also reported alongside adverse event data, with the authors characterizing the safety and efficacy profiles as satisfactory. Key limitations include the retrospective, non-randomized, single-arm design; the small and heterogeneous patient population spanning multiple tumor types; a median follow-up of only 13.7 months, which may be insufficient to assess long-term survival and late toxicities; and the absence of a control group, making it difficult to isolate Tα1's contribution. The authors acknowledge these findings are exploratory and call for larger, randomized, homogenous cohort studies to validate results.
Cancer management and research · Nov 2025DOI ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (active not recruiting). The purpose of this study is to evaluate the efficacy and safety of retatrutide compared with placebo for body weight reduction. Participation in the study will last about 65 weeks and may include about 18 visits.
ClinicalTrials.gov · Nov 2025View trial ↗ Animal only
This mouse study examined how acute restraint stress (30 minutes) interferes with hunger-driven food-seeking behavior and what interventions can reverse this effect. Using a conflict-based open-field feeding paradigm, researchers found that restraint stress abolished the increases in food seeking and intake normally observed in fasted mice. Two pharmacological interventions — intraperitoneal diazepam (an anxiolytic) and MK-677 (a ghrelin receptor agonist) — both reversed this stress-induced suppression of feeding behavior, though through apparently distinct neural mechanisms. To map neural correlates, the study measured c-Fos (a marker of neuronal activation) and phosphorylated pyruvate dehydrogenase (pPDH, a marker of neuronal inhibition) in the paraventricular hypothalamic nucleus (PVN). Diazepam reduced restraint-induced c-Fos expression in the PVN, suggesting anxiolysis works via suppressing stress-driven PVN activation, while MK-677 increased pPDH, indicating a separate feeding-drive mechanism. Notably, refeeding after fasting produced a pPDH-dominant PVN pattern and also reduced anxiety-related behaviors, suggesting physiological restoration of energy balance may itself confer stress resilience. Key limitations include exclusive use of a mouse model, the use of a single stress paradigm, and the lack of direct causal circuit manipulations. Findings are not directly applicable to humans without further study.
Neuroscience research · Nov 2025DOI ↗ Insufficient
The DREAMS-3 trial is a randomized, open-label Phase 3 study designed to compare the efficacy and safety of mazdutide (a glucagon receptor/GLP-1 receptor co-agonist) versus semaglutide (a GLP-1 receptor agonist) in Chinese adults with type 2 diabetes (T2D) and obesity. This publication reports the trial's rationale, design, and baseline characteristics rather than outcome results, as the study is ongoing with an expected completion date in early 2026. A total of 349 participants (mean age 42.4 years; 44.7% male) were randomized 1:1 to either treatment arm for a 32-week active-controlled period followed by a 24-week extension. At baseline, participants had a mean HbA1c of 8.0%, body weight of 90.5 kg, and BMI of 33.0 kg/m². The mean T2D duration was 1.8 years, and approximately 39.5% were on metformin. The primary endpoint is the proportion of participants achieving HbA1c targets. Notably, comorbidities such as metabolic-associated fatty liver disease and gout/hyperuricemia showed strong associations with BMI. As a design and baseline data paper, no efficacy or safety outcomes are yet available, limiting current evidence value.
Contemporary clinical trials · Nov 2025DOI ↗ Review
This paper examines the socioeconomic and systemic barriers that limit equitable access to glucagon-like peptide-1 (GLP-1) receptor agonist medications as obesity treatments. The authors note that obesity disproportionately burdens socioeconomically disadvantaged populations, yet the high cost and limited supply of GLP-1 agonists mean these effective therapies remain largely accessible only to those who can afford to pay privately. The paper frames this disparity through Julian Tudor Hart's "inverse care law," which describes how access to effective healthcare tends to be inversely correlated with clinical need. The authors argue that current rollout patterns risk deepening existing health inequalities rather than alleviating them. They call for evidence-informed policies to prioritize access based on clinical need, equitable global distribution strategies, and complementary investment in preventive and population-level public health measures. As a narrative review and commentary, the paper does not present original clinical data or trial results, and its conclusions are based on synthesized existing evidence and policy analysis rather than empirical study. Its primary value is as a framework for health policy discussion around GLP-1 access equity.
🧪 TrialInsufficient
Registered Phase 2 interventional trial (recruiting). This is a 28-week, single-arm, open-label phase II clinical trial evaluating the combination of Tirzepatide and remote, supervised, tailored resistance exercise training to achieve weight loss in adult survivors of childhood acute lymphoblastic leukemia (ALL) living with obesity or overweight with comorbidity. Primary Objective(s): • To evaluate the effectiveness for weight loss of the combined intervention using once weekly Tirzepatide plus remote, supervised, tailored resistance exercise (three sessions per week) in adult survivors of chi
ClinicalTrials.gov · Nov 2025View trial ↗ Review
This review synthesizes current scientific understanding of ghrelin, a hormone originally characterized primarily for its role in appetite stimulation and growth hormone release. The authors trace the full arc of ghrelin biology: from its biosynthesis (preproghrelin processing and O-acylation by the enzyme GOAT to produce the active acyl-ghrelin form), through its receptor pharmacology at GHSR1a, to its wide-ranging physiological roles. The review highlights that des-acyl ghrelin—the predominant circulating form—can exert effects independently of or with lower potency at GHSR1a, and that truncated "mini-ghrelins" may act as competitive antagonists. Recent cryo-EM structural data on GHSR1a are discussed as a framework for understanding biased signaling and drug design. The authors also review ghrelin's roles in glucose regulation, gastric function, cardiovascular tone, bone remodeling, renal hemodynamics, innate immunity, and the central nervous system—including links to neuroprotection, depression, Alzheimer's disease, and addiction. Translational topics covered include ghrelin stabilization strategies, synthetic ligands (agonists, antagonists, inverse agonists), LEAP-2-based approaches, and GOAT inhibitors. As a narrative review, the paper does not generate new experimental data, so primary evidence quality depends on the underlying cited studies.
International journal of molecular sciences · Nov 2025DOI ↗ 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 ↗ 🧪 TrialInsufficient
Registered Phase 1 interventional trial (recruiting). The purpose of this study is to investigate how the duration of fasting and temporary stopping of Glucagon-Like-Peptide 1 (GLP-1) medications affect the amount of food left in the stomach in people using liraglutide (injected), semaglutide (taken by mouth) or semaglutide (injected). The length of participants participation in the study will depend on the type of GLP-1 RA treatment participants are already using.
ClinicalTrials.gov · Nov 2025View trial ↗ 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 ↗