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GLP-1 receptor agonists in primary care: readiness, equity, and the risk of a two-tiered obesity treatment landscape.
Ther Adv Endocrinol Metab
Mohamed Mustaf Ahmed, Rahmatullah Nazari, Zhinya Kawa Othman +6 more
Glucagon-like peptide-1 receptor agonists have transformed obesity pharmacotherapy by producing substantial weight loss and, for semaglutide in patients with established cardiovascular disease, reducing major cardiovascular events. Integrating these therapies into primary care is constrained by gaps in provider training, clinical inertia, weight bias, high treatment costs, and fragmented insurance coverage. Racial and ethnic minority groups, low-income communities, and publicly insured patients are less likely to receive or fill prescriptions despite the disproportionate burden of obesity-related diseases. This narrative review examines primary care readiness, structural determinants of access, disparities in prescribing and use, real-world adherence, and policy options for these drugs. Without coordinated action, these therapies may reinforce a two-tiered treatment landscape in which access reflects socioeconomic advantages rather than clinical needs. Equitable implementation will require aligned reforms in coverage and pricing, workforce development, person-centered care, and long-term treatment support.
Adult Annular Pancreas Presenting With Gastric Outlet Obstruction Following Semaglutide Initiation: A Case Report.
Cureus
Fatima Gamaleldin, Milind Raje, Solomon K John
Annular pancreas is a rare congenital anomaly that may remain clinically silent until adulthood. Its symptoms can be masked or exacerbated by glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which delay gastric emptying. We report a 55-year-old male with type 2 diabetes who developed progressive postprandial vomiting and nine-kg weight loss following semaglutide initiation. Imaging revealed a partial annular pancreas causing second-part duodenal stenosis without malignancy. Symptoms persisted despite semaglutide discontinuation, supporting a fixed mechanical obstruction as the primary aetiology. The patient underwent successful Roux-en-Y gastrojejunostomy and cholecystectomy; histopathology confirmed benign fibrotic pancreatic tissue. At follow-up, the patient was symptom-free with nutritional recovery. This case emphasises that severe gastrointestinal symptoms in patients on GLP-1 RAs should prompt evaluation for structural pathology rather than being attributed solely to medication side effects, ensuring timely surgical intervention.
A Systematic Review and Meta-Analysis Evaluating the Role of GLP-1 Receptor Agonists in Substance Use Disorders.
Cureus
Indrani Sarma, Krishna P Biswas, Prerna Jagdish +3 more
GLP-1 receptor agonists (GLP-1RAs) have shown preclinical effects on reward-seeking behavior across several substance classes, but human randomized controlled trial (RCT) evidence remains limited. This systematic review and meta-analysis evaluated the effects of GLP-1RAs on substance-use outcomes in adults with substance use disorders. Electronic databases and trial registries were searched from inception to April 30, 2026, for parallel-group or crossover RCTs comparing any GLP-1RA with placebo or control. Outcomes included days without alcohol consumption, cigarettes smoked per day (CPD), and Fagerström Test for Nicotine Dependence (FTND) scores. Five RCTs met the inclusion criteria, including 764 participants with follow-up ranging from six to 52 weeks. Three RCTs contributed alcohol-related outcomes, and four contributed tobacco-related outcomes. Random-effects meta-analysis showed no statistically significant effect on days without alcohol consumption (MD -1.96 days, 95% CI -17.97 to 14.05; I² = 74%), CPD (MD -0.55 cigarettes/day, 95% CI -1.76 to 0.65; I² = 45%), or FTND score (MD 0.02, 95% CI -0.32 to 0.36; I² = 0%). Risk-of-bias assessment using the Cochrane Risk-of-Bias (RoB) 2 tool rated three trials as low risk overall and two as having some concerns. Certainty of evidence assessed using GRADE (Grading of Recommendations, Assessment, Development and Evaluations) ranged from low to moderate. Current pooled RCT evidence does not demonstrate a statistically significant benefit of GLP-1RAs for alcohol or tobacco use outcomes. A possible signal of benefit in patients with comorbid alcohol use disorder and obesity should be interpreted as hypothesis-generating because of the small number of trials, clinical heterogeneity, and imprecision. Adequately powered, long-duration, agent-specific RCTs using standardized substance-use outcomes are required before clinical translation can be recommended.
Targeting cellular senescence alleviates bone marrow aging.
bioRxiv
Bowen Yan, Jin Han, Yang Yang +14 more
Aging of the hematopoietic system impairs hematopoietic stem cell (HSC) function and alters bone marrow niche behavior, increasing susceptibility to anemia, infections, and hematologic malignancies. Here, pharmacologic clearance of senescent cells with the PROTAC compound 753b simultaneously targeting BCL-xL and BCL-2 reverses key secretory, transcriptional, and functional hallmarks of hematopoietic aging with low toxicity, restoring balanced lineage output. Single-cell RNA sequencing further demonstrates that 753b treatment attenuates aging-associated transcriptional signatures in HSCs, while selectively eliminating senescent, pro-survival niche cells without grossly perturbing niche composition. Functionally, 753b suppresses pro-inflammatory cues from both niche and hematopoietic cells including those emanating from neutrophil progenitors, rebalancing global bone marrow secretory ecosystem across stromal and hematopoietic compartments. Collectively, we identify 753b-induced senescent cell clearance as a powerful strategy to rejuvenate aged hematopoiesis and re-establish homeostatic communication between HSCs and their microenvironment, with implications for mitigating age-related hematologic dysfunction and improving hematologic health in older individuals.
A canine brain bank for comparative neuroscience and brain aging research.
bioRxiv
Sarah Darcy, Autumn Beck, Macy Garrood +6 more
Companion animal brain banking has been recognized as a valuable approach for translational aging and dementia research. However, realizing the full value of canine brain banks depends on optimizing the methods that are used to collect and preserve the tissue. Whole brain perfusion fixation is one promising approach, but it is not yet well described in dogs. Here we describe the development of methods for a canine brain bank (currently n = 55), including whole brain perfusion fixation via aortic cannulation and brain extraction. We assessed perfusion quality using gross examination, post-perfusion CT, and histological clearance of blood vessels. We found that body weight and average flow rate per body weight were each significantly correlated with perfusion quality in our cohort. To illustrate the kind of analysis the bank could facilitate, we next performed a preliminary study of brain aging, one of our primary planned research applications. Using a pixel classifier applied to whole slide images, we quantified lipofuscin burden, and in this preliminary cohort found that it increased strongly with age in both the thalamus and hippocampus. In the hippocampus, lipofuscin burden was also elevated in dogs with owner-reported cognitive dysfunction, although the current cohort is too small to determine to what extent this association is independent of age. Preliminary electron microscopy studies also confirmed that perfusion fixed tissue from the bank is amenable to ultrastructural analysis. This work describes one approach for canine brain perfusion fixation and introduces a brain tissue resource that may help support future neuroscience research.
Omega-3 fatty acids as modulators of advanced glycation end products in aging: mechanistic pathways and clinical implications - a narrative review.
Front Aging
Anna Cortesi, Irene P Tzanetakou, Konstantinos Giannakou +2 more
Aging is characterised by the progressive accumulation of advanced glycation end products (AGEs), formed through non-enzymatic glycation reactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs contribute to tissue damage through irreversible protein cross-linking and receptor-mediated inflammatory signalling via the receptor for AGEs (RAGE). Elderly individuals are disproportionately affected due to cumulative oxidative stress, chronic low-grade inflammation (inflammaging), impaired renal and enzymatic clearance, and prolonged exposure to dietary AGEs. Omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may modulate these pathways through anti-inflammatory, antioxidant, and metabolic mechanisms.
Exercise-Induced Plasma Surfactant Protein B Response in Advanced Heart Failure: Relation to Exercise Limitation, Resting Invasive Hemodynamics, and Clinical Outcomes.
Int J Mol Sci
Anna Drohomirecka, Katarzyna Kozar-Kamińska, Joanna Waś +4 more
Plasma surfactant protein B (SPB) is a marker of alveolar-capillary barrier injury and is elevated in heart failure (HF). We assessed whether cardiopulmonary exercise testing (CPET) changes plasma SPB in advanced HF and whether the SPB response relates to exercise limitations, resting pulmonary hemodynamics, and outcomes. Fifty-one patients (mean age 55.6 ± 7.5 years) with advanced HF (NYHA II-III, left ventricular ejection fraction ≤ 35%) underwent comprehensive evaluation, including CPET and invasive hemodynamic assessment. Blood samples were collected before and after CPET. Patients were followed for 23.5 ± 12.6 months. The composite endpoint included death, urgent heart transplantation, or left ventricular assist device implantation. SPB concentrations increased after CPET (median [IQR]: 77.5 [60.5-106.5] vs. 87.2 [63.5-111.9] ng/mL; p < 0.001). Greater relative increases occurred in NYHA III patients and correlated with NT-proBNP. Relative SPB changes correlated positively with the VE/VCO2 slope and negatively with the anaerobic threshold but not with resting systolic pulmonary artery pressure or pulmonary vascular resistance. Neither baseline nor post-exercise levels, nor their changes, predicted clinical outcomes. In conclusion, the SPB response to exercise reflects dynamic pulmonary barrier stress related to functional limitations in advanced HF but lacks prognostic value in this cohort.
Association Between Serum Leucine and NT-proBNP Levels in Relation to Fragmented QRS: A Multiomic Analysis of the HOZUGAWA Cohort.
Nutrients
Kunimasa Yagi, Hiroshi Okada, Masahide Hamaguchi +4 more
Branched-chain amino acids (BCAAs) may play a protective role in the progression of heart failure; however, controversial results also exist. This study investigates the association between fasting serum BCAA levels and plasma NT-proBNP concentrations in individuals with fragmented QRS (fQRS) on ECGs within the HOZUGAWA health-checkup cohort in Japan, offering insights into cardiac health.
Adrenal rather than central dysfunction limits hypothalamic-pituitary-adrenal axis recovery after chronic glucocorticoid treatment in male mice.
Endocrinology
Lindsey S Gaston, Brenna C Jorgensen, Hannah R Friedman +2 more
Glucocorticoid-induced adrenal insufficiency (GIAI) can persist for months after discontinuation of chronic corticosteroid therapy, placing patients at risk for life-threatening adrenal crises. This prolonged suppression has been attributed primarily to delayed restoration of hypothalamic-pituitary signaling based on indirect measures of central axis activity. To identify the rate-limiting site of hypothalamic-pituitary-adrenal (HPA) axis recovery, we evaluated the timing of functional and histologic recovery at each node of the axis following 8 weeks of dexamethasone (DEX) treatment in adult, male mice. Dexamethasone administration fully suppressed HPA axis activity. Unexpectedly, within 1 week of DEX withdrawal, hypothalamic Crh mRNA and plasma adrenocorticotropic hormone (ACTH) rebounded above control levels, whereas corticosterone (CORT) remained suppressed for an additional 7 weeks. Dexamethasone-treated adrenals were markedly atrophic and contained large clusters of lipid-filled macrophages. Even after adjusting for macrophage content, CORT secretion was disproportionately low relative to the remaining adrenocortical cell mass despite supraphysiologic ACTH stimulation. The adrenal is thus the principal site of postwithdrawal GIAI, involving adrenocortical cell loss and a superimposed defect in steroidogenesis. We next tested whether preserving adrenal trophic signaling during glucocorticoid exposure could prevent GIAI. Adrenal function recovered more slowly in mice treated with DEX and daily cosyntropin (a synthetic ACTH analog) compared to those treated with DEX alone. In contrast, mice with nonsuppressible endogenous ACTH due to targeted hypothalamic deletion of the glucocorticoid receptor maintained normal adrenal architecture and steroidogenic capacity despite prolonged DEX treatment. Pharmacologic treatments that mimic sustained trophic signaling to the adrenal during chronic glucocorticoid treatment may thus prevent GIAI.
Incretin-based therapies, alcohol and tobacco use, and acute substance-related events: emerging implications for cardiovascular medicine.
J Cardiovasc Pharmacol
Ovidio De Filippo, Francesco Bruno, Federico Giacobbe +7 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual incretin agonists are now familiar drugs in obesity, diabetes, heart failure, and cardiovascular prevention. At the same time, a clinically relevant but molecule-specific human literature suggests that selected incretin-based therapies, particularly semaglutide for alcohol-related outcomes, may also modify alcohol use, tobacco use, and selected acute substance-related events. Alcohol currently has the strongest signal. Small randomized studies suggest semaglutide can reduce laboratory alcohol self-administration and craving, whereas an earlier exenatide trial was neutral overall but suggested benefit in participants with obesity. Large registry and EHR studies further associate GLP-1RA exposure with lower alcohol-related hospitalization, lower incident or recurrent alcohol use disorder, and lower alcohol-related event rates. Tobacco evidence is more limited but now includes a pilot smoking-cessation trial with exenatide and a target-trial emulation linking semaglutide with fewer tobacco use disorder-related healthcare encounters. Evidence beyond alcohol and tobacco, and tirzepatide specific evidence, remains preliminary, although lower rates of opioid overdose, alcohol intoxication, and cannabis use disorder have been reported in observational analyses. For cardiologists, the key question is not whether incretin therapies should be viewed as addiction drugs, but whether established cardiometabolic therapies may also modify cardiovascular relevant risk behaviors.
Is amyloid beta peptide a driver of inflammaging?
Ageing Res Rev
Olga I Kechko, Alexey A Moskalev, Claudio Franceschi +2 more
Inflammaging, the chronic subclinical systemic inflammation accompanying aging, represents a critical pathogenetic mechanism underlying age-related neurodegenerative diseases. While amyloid beta (Aβ) peptides are established contributors to neuroinflammation in Alzheimer's disease, their role in aging-related subclinical inflammation remains insufficiently elucidated. In humans, Aβ exhibits dual functions: it supports neuronal activity, survival, and protection against neurotrauma, while also promoting inflammation and central nervous system dysfunction. This review highlights the beneficial effects of Aβ, including its antioxidant and antipathogenic properties, and synthesizes current knowledge of the molecular mechanisms driving Aβ-associated inflammaging. We structure this analysis across distinct brain cell types - microglia, astrocytes, oligodendrocytes, neurons, pericytes, and endothelial cells - and consider additional factors influencing Aβ-related neuroinflammation. Finally, we examine strategies to counteract the detrimental effects of Aβ, focusing on Aβ physiological clearance via the blood-brain barrier and glymphatic system, as well as therapeutic interventions. Understanding Aβ-driven inflammaging mechanisms offers new therapeutic avenues for early intervention in age-related neurodegenerative diseases, particularly in genetically susceptible populations. Targeting Aβ-associated inflammaging reframes Aβ not solely as a pathological marker but also as a context-dependent contributor to inflammatory processes during brain aging.
Temporal changes in BNP levels and their prognostic impact on future cardiac events in patients undergoing transcatheter aortic valve implantation.
Int J Cardiol
Koji Mizutani, Akihito Tanaka, Yoshiyuki Tokuda +8 more
Detailed patterns of changes in brain natriuretic peptide (BNP) levels during the perioperative period and long-term follow-up after transcatheter aortic valve implantation (TAVI) and the prognostic significance of these BNP levels have not been fully elucidated.
Cardiovascular Autonomic Neuropathy and Indices of Heart Failure in Type 2 Diabetes: The CANCAN Study.
Diabetes Obes Metab
Jonas R Schaarup, Lasse Bjerg, Christian S Hansen +5 more
To quantify the association between cardiovascular autonomic neuropathy (CAN) and heart failure (HF) in individuals with type 2 diabetes (T2D).
Differential Anti-Inflammatory Effects of Semaglutide and Tirzepatide in Experimental Diabetes Mellitus.
Curr Issues Mol Biol
Roxana-Cristina Dobriceanu, Ianis Kevyn Stefan Boboc, Liliana Mititelu Tartau +6 more
Type 2 diabetes mellitus is associated with chronic low-grade inflammation contributing to endothelial dysfunction, metabolic imbalance, and cardiovascular complications. Although semaglutide (SEM) and tirzepatide (TIR) provide important metabolic and cardioprotective benefits, their early anti-inflammatory effects and potential sex-dependent differences remain incompletely understood. This study comparatively evaluated the effects of SEM and TIR on systemic inflammatory biomarkers in a murine model of streptozotocin-induced diabetes mellitus. Thirty BALB/c mice were allocated into six experimental groups according to sex and treatment: control, SEM, and TIR groups (n = 5/group). Diabetes was induced by intraperitoneal streptozotocin administration, followed by treatment with SEM or TIR. Circulating interleukin-1β (IL-1β) and pentraxin-3 (PTX-3) levels were measured at baseline, one week after streptozotocin administration, and after six weeks of treatment. Control groups exhibited progressive increases in IL-1β and PTX-3 levels, indicating sustained inflammatory activation. In contrast, SEM- and TIR-treated animals showed attenuated inflammatory responses characterized by transient or stabilized biomarker profiles. Differential inflammatory responses were observed between treatments and sexes. Male SEM and Male TIR groups demonstrated stable IL-1β levels, whereas female treated groups showed persistent elevations, particularly Female TIR animals. PTX-3 responses also displayed differential sex-dependent patterns, with Female SEM animals exhibiting the most stable inflammatory profile. These findings suggest differential early immunomodulatory effects of the two modern antidiabetic drugs, characterized by distinct biomarker responses according to sex and inflammatory marker profile. IL-1β and PTX-3 may represent complementary biomarkers for the assessment of early inflammatory activation associated with diabetes mellitus and its cardiometabolic complications.
Real-World Kidney and Glycaemic Outcomes Following Semaglutide Initiation in Adults with Type 2 Diabetes and Mild Chronic Kidney Disease.
J Clin Med
Syed Arman Rabbani, Haea Amar Alkoud, Mohamed El-Tanani +5 more
Background: Real-world kidney and metabolic responses to semaglutide in type 2 diabetes (T2D) and chronic kidney disease (CKD) remain poorly characterised, particularly in Middle East and North Africa (MENA) region. Methods: We conducted a retrospective, single-centre, paired-cohort study at a secondary care hospital in UAE. Adults with T2D and predominantly mild CKD newly initiated on subcutaneous semaglutide were included. Single-arm design without comparator; findings describe biomarker trajectories and cannot establish causality. Primary outcomes were within-participant six-month changes in serum creatinine, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (uACR). Results: A total of 324 patients were analysed (mean age 55.3 ± 12.4 years; 66.0% female; BMI 36.1 ± 6.9 kg/m2; median HbA1c 8.3% [IQR 7.2-10.0]; eGFR 87.0 ± 25.8 mL/min/1.73 m2; KDIGO G1-G2 in 82.7%; A2 92.6%, A3 4.6%). At six months, BMI fell by 2.0 kg/m2 and HbA1c by a median 2.0%; 52.0% achieved ≥5% BMI reduction and 87.2% achieved ≥0.5% absolute HbA1c reduction. Serum creatinine decreased by 3.6 µmol/L and eGFR rose by 3.7 mL/min/1.73 m2; given concurrent weight loss, these changes likely reflect reduced creatinine generation rather than true filtration improvement. A ≥30% eGFR decline occurred in only 0.9%. Geometric mean uACR fell by 19.8%; among participants with baseline uACR ≥ 30 mg/mmol, 66.7% achieved ≥30% uACR reduction. KDIGO G-category improved in 17.3% and was stable in 76.8%; the A-category remained stable in 95.7%. Conclusions: In adults with T2D, mild CKD, and substantial obesity, semaglutide was associated with clinically meaningful improvements in weight, glycaemia, and albuminuria over six months, supporting it as part of a layered cardio-renal protective strategy in routine care.
Understanding Obesity as a Multisystem Disease: Advancing Research, Redefining Diagnostic Criteria, and Establishing Modern Therapeutic Approaches.
Nutrients
Hala Abdallah, Mohamad Khalil, Laura Mahdi +4 more
Obesity is a complex, chronic, relapsing disease that affects nearly all physiological functions and homeostatic mechanisms, extending far beyond mere excess adiposity. Traditional clinical practice often relies on uniform interventions that fail to account for diverse patient phenotypes. This review synthesizes current evidence on personalized obesity management, dietary interventions, and advanced pharmacotherapies aligned with the new 2025 Lancet Commission framework. A comprehensive narrative review was conducted across major biomedical databases to evaluate the efficacy, safety, and mechanisms of metabolic interventions, focusing on phenotype-specific dietary matching, bioactive compounds, and modern multi-receptor glucagon-like peptide-1 (GLP-1)-based therapies across preclinical and clinical intervention tiers in adult and pediatric populations. While specific nutraceutical extracts display promising secondary metabolic benefits, their overall weight-loss efficacy remains modest due to variable clinical data and limited sample sizes. Conversely, high-potency anti-obesity medications demonstrate unprecedented weight-reduction efficacy, with semaglutide 2.4 mg and tirzepatide yielding mean body weight losses of ~14.9% and ~20.9%, respectively. Furthermore, landmark outcome data from the SELECT trial confirms that semaglutide 2.4 mg achieves a significant 20% relative risk reduction in major adverse cardiovascular events (MACE), independent of baseline glycemic status or heart failure. However, clinical extension data reveal rapid weight rebound upon drug cessation, highlighting that obesity requires continuous, long-term therapeutic strategies. Effective obesity care demands an operational shift from traditional, one-size-fits-all treatments to personalized, multi-tiered strategies. Combining phenotype-specific lifestyle modifications with potent, long-term multi-hormonal pharmacotherapies or metabolic surgery optimizes long-term therapeutic durability, systemic metabolic health, and sustained cardioprotection.
Dose-dependent effects of oral semaglutide on arterial stiffness and the additive role of SGLT-2 inhibitors in type 2 diabetes.
Br J Clin Pharmacol
Takao Sato, Toshihiro Miyamoto, Ryoma Fukuoka +7 more
The cardio-ankle vascular index (CAVI) is a blood pressure-independent marker of arterial stiffness and a well-established predictor of cardiovascular (CV) events. The effects of oral semaglutide, particularly at low doses, on arterial stiffness remain unclear.
Correction: Exploring factors predicting the effectiveness of oral semaglutide in Japanese individuals with type 2 diabetes switching from dipeptidyl peptidase 4 inhibitors: a pilot study.
Front Clin Diabetes Healthc
Takao Hirotsu, Kanta Taniguchi, Rimei Nishimura
[This corrects the article DOI: 10.3389/fcdhc.2025.1520389.].
Unconventional Applications of Semaglutide and Tirzepatide: From Oncology to Human Reproduction.
Biomedicines
Sandro La Vignera, Rosita A Condorelli
Semaglutide and tirzepatide, glucagon-like peptide-1 (GLP-1) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists, respectively, have revolutionized the management of type 2 diabetes mellitus and obesity. Beyond their established metabolic indications, emerging preclinical and clinical evidence suggests these incretin-based therapies exert pleiotropic effects across multiple organ systems through mechanisms extending beyond glycemic control and weight reduction. This comprehensive review synthesizes current evidence for unconventional applications of semaglutide and tirzepatide across five distinct therapeutic domains: oncology, psychiatry and addiction medicine, orthopedics, aesthetic medicine, and human reproduction. In oncology, both agents demonstrate antitumor activity primarily through immune and metabolic reprogramming rather than direct cytotoxicity, with promising signals in pancreatic, thyroid, breast, and colorectal cancers. In psychiatry, modulation of mesolimbic dopamine reward pathways and GABAergic neurotransmission underlies robust preclinical and observational evidence for reducing alcohol use disorder, substance use, and binge-eating behaviors. Orthopedic applications include clinically meaningful improvements in knee osteoarthritis pain and function, though bone health signals remain mixed. Aesthetic medicine faces the dual challenge of managing GLP-1 receptor agonist-associated facial volume loss while exploring therapeutic potential in inflammatory dermatoses. In reproductive medicine, metabolic improvements translate to benefits in polycystic ovary syndrome and male fertility, though periconception safety concerns persist. Across all domains, evidence derives predominantly from preclinical models, observational cohorts, and pharmacoepidemiologic studies, with randomized controlled trials remaining limited. This review critically evaluates mechanisms, efficacy signals, safety considerations, and research priorities for each application domain, providing a roadmap for translating unconventional uses of semaglutide and tirzepatide into evidence-based clinical practice.
Beyond GLP-1 Agonists: Plant-Derived Bioactive Compounds as Adjunctive Strategies for Obesity Management.
Nutrients
Aurelian Vasile, Andrei Cristian Anghel, Teodor Ioan Trasca +1 more
Background: Obesity has reached epidemic proportions, affecting over one billion adults worldwide. While incretin-based pharmacotherapies-GLP-1 receptor agonists (semaglutide) and dual GIP/GLP-1 agonists (tirzepatide)-have transformed obesity treatment, their use remains limited by high costs, adverse effects, restricted eligibility, and rapid weight regain following discontinuation. Plant-derived bioactive compounds represent a promising complementary approach to address these gaps. Objective: This narrative review synthesizes clinical trial evidence on plant-based interventions for obesity management and examines their potential role as adjunctive strategies before, during, and after incretin-based pharmacotherapy. Methods: A literature search was conducted in PubMed, Scopus, and Web of Science (2012-2026), prioritizing randomized controlled trials in adults with overweight or obesity reporting at least one obesity-related metabolic outcome. Sixty-one studies were selected and classified by efficacy tier based on the magnitude and breadth of observed clinical effects. Results: The strongest evidence supports polyphenol-rich dietary patterns, particularly the green-Mediterranean diet, producing significant reductions in body weight, visceral fat, and cardiometabolic risk markers. Specific extracts-including curcumin, bergamot polyphenols, and Lippia citriodora/Hibiscus sabdariffa combinations-demonstrated clinically meaningful metabolic improvements. Isolated high-dose resveratrol and several single-compound interventions showed limited benefit, largely attributable to poor bioavailability. The most effective compounds acted through multiple pathways, including AMPK activation, gut microbiota modulation, and appetite hormone regulation. Conclusions: Plant-derived bioactive compounds offer a safe, accessible adjunctive strategy for obesity management, particularly relevant for patients ineligible for or discontinuing pharmacotherapy. Future trials should directly evaluate plant-polyphenol combinations alongside GLP-1 receptor agonists.