Review
This narrative review examines the problem of lean body mass (LBM) loss associated with weight loss, with particular focus on incretin-based therapies such as GLP-1 receptor agonists (e.g., semaglutide) and dual GIP/GLP-1 receptor agonists (e.g., tirzepatide). The authors queried PubMed, Medline, and Scopus for randomized controlled trials and Phase II/III trials related to obesity, muscle loss, and lean mass preservation, excluding animal studies. The review outlines the physiological mechanisms driving muscle loss during caloric deficit—including reduced anabolic signaling, increased protein catabolism, and hormonal changes—and surveys pharmacological agents under investigation to counteract these effects. Key drug classes discussed include bimagrumab (an activin receptor antagonist targeting the myostatin pathway), tesamorelin (a growth hormone-releasing hormone agonist), and enobosarm (a selective androgen receptor modulator). The authors note that while incretin-based therapies represent a major advance in obesity management, the accompanying loss of muscle mass is a clinically meaningful concern. Most agents targeting LBM preservation are in early research phases. Limitations include reliance on narrative rather than systematic methodology, potential selection bias in study inclusion, and the rapidly evolving evidence base in this area.
Journal of clinical medicine · Jan 2026DOI ↗ Limited · human
This retrospective cohort study used the TriNetX Global Collaborative Network to investigate whether GLP-1 receptor agonist (GLP-1 RA) therapy is associated with an increased risk of nonarteritic anterior ischemic optic neuropathy (NAION) in adults with type 2 diabetes mellitus (T2DM). Researchers divided patients into two groups: those with T2DM receiving GLP-1 RA treatment and those with T2DM not receiving GLP-1 RAs. After one-to-one propensity-score matching on 20 covariates, each cohort contained 388,333 patients. Over a five-year follow-up period, the GLP-1 RA-treated cohort showed a statistically significant higher risk of NAION (risk ratio 1.339, 95% CI 1.137–1.577; risk difference 0.022%; p = 0.005). An E-value sensitivity analysis suggested the association was moderately robust to unmeasured confounding. The authors caution that the absolute risk difference is small and that GLP-1 RAs carry well-established cardiovascular and metabolic benefits. Key limitations include the retrospective, observational design using de-identified administrative data, potential residual confounding, and an inability to confirm causality. The authors call for prospective studies to clarify the mechanism and refine clinical guidelines.
Review
This state-of-the-art narrative review examines the potential role of innovative diabetes therapies — specifically incretin-based therapies (GLP-1 receptor agonists), SGLT2 inhibitors, and emerging dual/triple receptor agonists — in modifying the course of diabetic peripheral neuropathy (DPN) and autonomic diabetic neuropathy. The authors synthesize evidence from preclinical models, clinical trials, and real-world observational studies, arguing that GLP-1 RAs and SGLT2 inhibitors may offer neuroprotective benefits beyond their established glucose-lowering effects, potentially through attenuation of inflammation and oxidative stress, improved mitochondrial function, and reduced neuronal damage. The review also highlights novel dual and triple receptor agonists as emerging agents with theoretical synergistic neuroprotective potential via simultaneous activation of multiple metabolic pathways. Limitations inherent to this paper include its narrative (non-systematic) design, which introduces selection bias, and the authors' own acknowledgment that clinical data on newer agents in the context of DN remain limited. The review does not generate new primary data. Overall, it provides a useful conceptual synthesis of an evolving therapeutic landscape but cannot establish causality or definitive efficacy for any agent in DN.
Diabetes therapy : research, treatment and education of diabetes and related disorders · Jan 2026DOI ↗ Review
This narrative review synthesizes mechanistic and clinical trial evidence on incretin-based therapies — GLP-1 receptor agonists (GLP-1RA), DPP-4 inhibitors, and newer dual/triple agonists — for cardiovascular (CV) and renal protection in type 2 diabetes (T2DM) and related conditions. The authors draw on multiple pivotal randomized cardiovascular outcome trials (CVOTs), including SELECT (semaglutide in obesity without diabetes), FLOW (semaglutide in chronic kidney disease), SOUL (oral semaglutide in T2DM with ASCVD/CKD), and SURPASS-CVOT (tirzepatide vs. dulaglutide). Key findings attributed to these trials include reductions in major adverse cardiovascular events (MACE), CV and all-cause mortality, heart-failure hospitalization, and hard kidney endpoints across GLP-1RA programs. A 2019 pooled analysis and a 2025 update reportedly confirm these cardiorenal benefits independent of baseline HbA1c. Mechanistically, the review describes GLP-1R signaling via Gs-cAMP/PKA, β-arrestin, and Gq pathways, linked to anti-inflammatory, natriuretic, and antifibrotic effects. Oral small-molecule GLP-1R agonists (e.g., orforglipron) showed phase 2 efficacy but lacked long-term outcome data at time of publication. As a narrative review, it is subject to selection bias and does not conduct formal meta-analytic pooling.
Diabetes therapy : research, treatment and education of diabetes and related disorders · Jan 2026DOI ↗ Review
This perspective article examines retatrutide (LY3437943), a novel triple receptor agonist that simultaneously targets GLP-1, GIP, and glucagon receptors, positioning it as a significant advancement in obesity pharmacotherapy. The authors contextualize retatrutide within the broader evolution of incretin-based therapies, arguing that its multi-hormonal mechanism addresses limitations of existing GLP-1 and dual GIP/GLP-1 agonists. The article highlights Phase 2 trial findings, which reportedly demonstrated weight reductions comparable to bariatric surgery, along with potential benefits for metabolic comorbidities including non-alcoholic steatohepatitis (NASH) and cardiovascular disease. The authors frame retatrutide as a proof-of-concept for rational multi-agonist peptide engineering and advocate for broader scientific engagement, health equity considerations, and proactive policy planning in anticipation of wider clinical adoption. As a perspective/review piece, this paper synthesizes existing evidence rather than presenting original trial data, and does not provide head-to-head comparisons or long-term safety data. Its conclusions are largely interpretive, and the characterization of Phase 2 findings as surgery-comparable warrants cautious interpretation pending Phase 3 results and regulatory review.
Clinical pharmacology in drug development · Jan 2026DOI ↗ Review
This review synthesizes evidence from approximately 108 priority studies—including RCTs, prospective cohorts, and mechanistic reports—identified through a systematic search of PubMed, Scopus, and Web of Science (2000–2025) to reframe heart failure with preserved ejection fraction (HFpEF) as a systemic cardio-metabolic syndrome rather than a purely cardiac condition. The authors argue that visceral adiposity, insulin resistance, chronic inflammation, and mitochondrial dysfunction collectively impair cardiac energetics and drive HFpEF pathophysiology. The review notes that conventional neurohormonal therapies (RAAS inhibitors, beta-blockers) showed neutral outcomes in heterogeneous HFpEF populations, whereas the landmark EMPEROR-Preserved and DELIVER RCTs demonstrated that SGLT-2 inhibitors reduced hospitalizations and cardiovascular events. GLP-1 receptor agonists were also reported to improve symptoms, exercise tolerance, and body weight, further supporting a metabolic-inflammation framework. The authors call for biomarker-driven patient phenotyping, advanced imaging, and adaptive trial designs to enable precision care. Limitations include the inherent heterogeneity of HFpEF populations and the reliance on synthesized rather than primary data, with mechanistic claims drawn partly from preclinical and observational sources.
Review
This narrative review synthesizes existing literature on obesity management strategies, drawing from PubMed, Scopus, ScienceDirect, and Google Scholar. It evaluates the comparative effectiveness, safety, sustainability, and real-world applicability of five broad intervention categories: lifestyle modifications, dietary approaches, behavioral therapy, pharmacotherapy, and bariatric or endoscopic procedures. Key findings reported by the authors include that lifestyle interventions, while foundational, are frequently undermined by physiological adaptations, behavioral challenges, and socioeconomic barriers. Dietary strategies tend to converge in weight-loss outcomes over time, with adherence emerging as the primary differentiator. Pharmacotherapy—particularly incretin-based agents such as GLP-1 receptor agonists and dual GIP/GLP-1 agonists—is highlighted as producing meaningful weight loss and cardiometabolic improvements, though the authors note concerns around cost, tolerability, and the need for continued use. Bariatric surgery is characterized as the most effective long-term option for severe obesity, with endoscopic procedures noted as an expanding alternative. Behavioral and psychological support is identified as a cross-cutting enabler of adherence. The authors conclude that personalized, multidisciplinary care is essential. As a narrative review, this paper does not conduct original data collection or meta-analysis, and findings are subject to selection bias inherent in non-systematic review methodology.
Journal of obesity · Jan 2026DOI ↗ Review
This review examines the evolving landscape of glucagon-like peptide-1 receptor agonist (GLP-1RA) therapies and their role in cardiorenal protection in metabolic diseases, particularly type 2 diabetes (T2D) and obesity. The authors synthesize evidence from clinical and real-world studies demonstrating that GLP-1RAs consistently reduce HbA1c and body weight, and that mounting data support cardiovascular and kidney benefits beyond glycaemic control in high-risk populations. The review highlights that in T2D, GLP-1RAs have been shown to improve hard cardiovascular outcomes and, more recently, kidney outcomes. In individuals with obesity without T2D, semaglutide at a higher dose was reported to reduce body weight by up to 15% and lower major adverse cardiovascular events by approximately 20%. The review also covers next-generation "multi-agonist" molecules combining GLP-1 receptor agonism with activity at GIP, glucagon, and amylin receptors, aiming for complementary or synergistic metabolic effects. Tirzepatide, a dual GLP-1/GIP receptor agonist approved for T2D and obesity, is highlighted as achieving up to 22.5% weight loss in phase 3 trials. Limitations include the inherent constraints of a narrative review: no new primary data are generated, and conclusions depend on the scope and quality of included studies.
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · Jan 2026DOI ↗ Review
This review examines the potential neuroprotective role of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) — a drug class established for managing type 2 diabetes and obesity — in the context of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The authors propose that neurodegeneration is driven by a self-reinforcing cycle of chronic neuroinflammation and central metabolic dysfunction, worsened by impaired insulin/IGF-1 signalling, mitochondrial dysfunction, and pro-inflammatory microglial activation triggered by misfolded protein aggregates. The review synthesizes preclinical and clinical trial data to argue that GLP-1RAs may disrupt this cycle via a dual mechanism: reducing central insulin resistance and directly suppressing neuroinflammatory cascades by modulating glial responses, inhibiting pro-inflammatory cytokines, and reducing oxidative stress in the CNS. The authors conclude that GLP-1RAs represent a promising, translatable therapeutic strategy for neurodegeneration and call for large-scale human trials. Limitations include the review's reliance on synthesizing heterogeneous preclinical and early clinical data, without original data collection, and the mechanistic conclusions remain to be validated in robust, adequately powered human studies.
Diabetes, obesity & metabolism · Dec 2025DOI ↗ Moderate · human
This Phase 3 randomized controlled trial evaluated mazdutide, a dual glucagon receptor (GCGR) and GLP-1 receptor (GLP-1R) agonist, as monotherapy versus placebo in 320 Chinese adults with type 2 diabetes (T2D) inadequately controlled by diet and exercise. Participants had a mean HbA1c of 8.24% and BMI of 28.2 kg/m². They were randomized 1:1:1 to weekly subcutaneous injections of mazdutide (4 mg or 6 mg) or placebo for 24 weeks, followed by a 24-week mazdutide extension phase. At week 24, the study found that both mazdutide doses significantly reduced HbA1c versus placebo (−1.57% and −2.15% for 4 mg and 6 mg, respectively, vs. −0.14% for placebo). Both doses also produced significantly greater body weight reductions and improved rates of composite endpoints (HbA1c <7.0% with ≥5% weight loss) compared to placebo. The most common adverse events—diarrhea, decreased appetite, and nausea—were consistent with the GLP-1R agonist class. Limitations include the single-ethnicity population (Chinese adults), the relatively short 24-week primary endpoint period, and the lack of an active comparator arm, which limits generalizability and comparative effectiveness conclusions.
Moderate · human
This Phase III randomized controlled trial evaluated mazdutide, a novel once-weekly dual glucagon and GLP-1 receptor agonist, compared to dulaglutide in 731 Chinese adults with type 2 diabetes (T2D) on background oral anti-diabetic therapy. Participants were randomized 1:1:1 to one of two mazdutide doses or dulaglutide (1.5 mg) for 28 weeks. The study found that both mazdutide doses demonstrated non-inferiority and superiority to dulaglutide in reducing HbA1c from baseline, with least-squares mean treatment differences of -0.24% and -0.30% for the lower and higher doses, respectively. Mazdutide also produced significantly greater reductions in body weight than dulaglutide, with differences of -3.78% and -5.76% for the two doses. The safety profile was generally acceptable, though gastrointestinal adverse events occurred more frequently with mazdutide than dulaglutide. Limitations include the relatively short 28-week duration, restriction to a Chinese population, and the lack of a placebo arm, which may limit generalizability of findings.
In vitro
This study describes the development of a high-yield Chinese hamster ovary (CHO) cell manufacturing platform for a biosimilar of dulaglutide, a GLP-1/IgG4-Fc fusion protein approved for type 2 diabetes. Researchers used apoptosis-resistant CHO 4BGD cells and sequentially transfected two expression plasmids encoding dulaglutide, employing a two-step transgene amplification strategy using methotrexate (MTX) followed by methionine sulfoximine (MSX) selection. The dual-selection approach resulted in approximately 30% higher titers in polyclonal populations compared to MTX amplification alone. Through a clonal cell line selection pipeline, the top clone (4BGD/Dul #73) achieved a product titer of 1.05 g/L in a 3-week fed-batch process, with a specific productivity of up to 22 pg·cell⁻¹·day⁻¹ and stable expression over 69 days without selective pressure. Purity assessed by size-exclusion HPLC showed ≥95% monomer content. Biological activity testing in a GLP-1 receptor/CRE-luciferase reporter assay yielded an EC₅₀ of 52 pM for the biosimilar candidate versus 76 pM for the reference drug. Limitations include the absence of in vivo or clinical data, with all findings limited to cell culture and in vitro bioassay systems.
Pharmaceuticals (Basel, Switzerland) · Dec 2025DOI ↗ Limited · human
This case report describes a 61-year-old woman with type 2 diabetes and morbid obesity who developed severe small bowel obstruction after more than a year of tirzepatide therapy. The patient experienced progressive constipation following initiation of tirzepatide, eventually presenting with acute diffuse abdominal pain and dry heaving. CT imaging revealed multiple dilated, fluid-filled small bowel loops with a transition point in the lower pelvis, moderate gastric distention, and free pelvic fluid. Initial conservative management with nasogastric decompression, bowel rest, intravenous fluids, and analgesia was insufficient, and the patient ultimately required laparoscopic adhesiolysis converted to exploratory laparotomy. Intraoperatively, a closed-loop obstruction caused by adhesive disease and an internal hernia was identified, necessitating resection of 25 cm of necrotic bowel. Pathology confirmed ischemic changes. Notably, tirzepatide had produced meaningful metabolic benefits, including hemoglobin A1c reduction and weight loss. The authors propose that tirzepatide's known effects on gastrointestinal motility may have worsened pre-existing constipation and contributed to the obstructive event in this predisposed patient. Key limitations include the single-patient design, the presence of confounding adhesive disease, and the inability to establish direct causation.
Limited · human
This study describes the development and validation of a urine-based liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for detecting semaglutide use in humans. Semaglutide is a GLP-1 receptor agonist originally approved for type 2 diabetes that has gained widespread use as a weight-loss aid. The authors note that semaglutide may confer a competitive advantage in weight-class sports (e.g., wrestling, boxing) by facilitating weight management, raising anti-doping concerns. The proposed method targets two unique urinary metabolites of semaglutide—designated U6 and U7—as biomarkers of exposure. Using only 2 mL of urine, the method achieved a reported limit of detection (LOD) of 50 pg/mL. The authors positioned this approach as a simpler alternative to existing blood-based testing regimens, given urine's relative ease of collection. Limitations include the absence of reported clinical validation data (e.g., pharmacokinetic profiling in dosed volunteers), no information on inter-individual variability, and no discussion of detection windows post-dose. The study is primarily an analytical methods paper rather than a clinical or pharmacological investigation.
Analytical and bioanalytical chemistry · Dec 2025DOI ↗ Review
This review article examines the evolving landscape of engineered nutrient-stimulated hormonal (NUSH) peptide therapies for obesity and related metabolic conditions, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease. The authors describe the mechanistic basis of GLP-1 receptor agonists (GLP-1RAs) and their limitations as monotherapies, then explore how dual and triple co-agonist strategies — combining GLP-1 with GIP, glucagon, amylin, or peptide YY — aim to overcome those gaps. The review highlights clinical and preclinical data for specific agents: tirzepatide (GLP-1/GIP), CagriSema (GLP-1/amylin), and retatrutide (GLP-1/GIP/glucagon), noting reported benefits in weight reduction, glycemic control, liver health, cardiovascular outcomes, and inflammation. The paper also discusses non-peptidyl oral GLP-1 RAs such as orforglipron as adherence-improving alternatives. The authors frame these multi-agonist therapies as a paradigm shift analogous to the pleiotropic hormonal effects of bariatric surgery, and as building blocks for precision metabolic medicine. As a narrative review, it does not generate new primary data, and conclusions depend on the quality and heterogeneity of the underlying cited studies.
Clinical and molecular hepatology · Nov 2025DOI ↗ Insufficient
This exploratory simulation study compared the quality of responses generated by a large language model (GPT-4o) versus standard internet searches (Google) when answering 17 common patient-style questions about GLP-1 receptor agonist (GLP-1RA) therapy for obesity. Questions were selected based on Google Trends data and covered indications, expected treatment course, side effects, and specific risks. Two independent evaluators scored responses using a 5-point Likert scale across six domains: safety, guideline consensus, objectivity, reproducibility, relevance, and explainability. The study found that LLM responses scored significantly higher than internet search results in objectivity and reproducibility, while no significant differences were observed in the remaining four domains. Interrater agreement was high (Gwet AC ≈ 0.879). Qualitatively, LLM responses were noted to lack coverage of emerging clinical issues due to static training data, whereas internet results were more current but often commercially biased and inconsistent. The authors conclude that LLMs may offer a more reliable and objective source of health information for patients, though human oversight and real-time data integration remain important limitations to address. The study is limited by its small, simulated question set and lack of real patient interaction data.
JMIR formative research · Nov 2025DOI ↗ Review
This narrative review examines the current and emerging landscape of GLP-1 receptor agonists (GLP-1RAs) as treatments for obesity and related metabolic conditions. The authors survey the three FDA-approved agents for obesity—liraglutide, semaglutide, and tirzepatide—alongside off-label options, summarizing evidence for their efficacy in weight reduction and glycemic control. The review also discusses expanding indications, including potential benefits in neurodegenerative disorders, fatty liver disease, dyslipidemia, atherosclerosis, cardiovascular disease, chronic kidney disease, and heart failure. Emerging pipeline agents—such as CagriSema, orforglipron, mazdutide, retatrutide, and survodutide—are highlighted alongside innovations like ultralong-acting formulations, combination therapies, higher-dose oral delivery, and AI-integrated drug development. The authors note that generic liraglutide and evolving insurance coverage may reshape affordability and access. Key limitations acknowledged include adherence challenges, safety concerns, disparities in global access, and the need for long-term data on sustained weight loss and disease modification. As a narrative review, the paper synthesizes existing literature rather than generating new primary data, and conclusions are therefore subject to the quality and selection of included studies.
Journal of obesity · Nov 2025DOI ↗ Animal only
This study investigated whether milk-derived small extracellular vesicles (sEVs) could serve as oral delivery vehicles for two GLP-1 receptor agonists (GLP-1RAs): semaglutide and tirzepatide. Researchers loaded both peptides onto sEVs in vitro and administered them orally to diabetic db/db mice—a well-established mouse model of type 2 diabetes. The study found that both peptides were efficiently incorporated into the sEV carrier system and that oral administration of the loaded vesicles effectively reduced blood glucose levels in the diabetic mice. The authors compared this approach to the existing SNAC (sodium N-[8-(2-hydroxybenzoyl) amino] caprylate) technology used in the commercially approved oral semaglutide formulation (Rybelsus), arguing that sEVs offer broader applicability across multiple peptide drugs, not just semaglutide. Key limitations include the exclusive use of an animal model with no human pharmacokinetic or efficacy data, a relatively small and homogeneous study design, and the early-stage, preclinical nature of the platform. Translation to humans remains undemonstrated.
Journal of extracellular biology · Nov 2025DOI ↗ Review
This scoping review examines the biological rationale and existing evidence for using glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the management of psoriatic disease (PsD), a chronic systemic inflammatory condition frequently accompanied by cardiometabolic comorbidities such as obesity, type 2 diabetes mellitus, and cardiovascular disease. The authors explored three main areas: (1) how obesity, diabetes, and cardiovascular disease influence PsD severity and treatment resistance; (2) the established efficacy of GLP-1RAs in managing these comorbidities; and (3) early evidence from rheumatologic and dermatologic conditions including rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, and hidradenitis suppurativa. The review highlights shared immunopathogenic mechanisms — particularly Th1/Th17-driven cytokines such as TNF, IL-6, and IL-17 — as a rationale for GLP-1RA use beyond metabolic indications. The authors report that early clinical and preclinical data suggest GLP-1RAs may reduce systemic inflammation and PsD burden, but acknowledge this evidence is preliminary. Key limitations include the scoping review design (which maps available evidence rather than synthesizes effect sizes), reliance on preclinical and indirect data, and the absence of dedicated randomized controlled trials in PsD populations. The authors conclude that further clinical trials are needed to establish disease-modifying potential.
Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 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 ↗