Review
This narrative review examines the rapidly evolving landscape of obesity pharmacotherapy, moving beyond currently approved injectable GLP-1 receptor agonists (GLP-1RAs). The authors contextualize the global obesity burden—affecting over 2 billion adults—and acknowledge the transformative but limited success of existing GLP-1-based therapies, citing weight loss plateaus, high inter-individual variability, and weight regain upon discontinuation as key unresolved challenges. The review synthesizes emerging drug classes including: oral GLP-1 agonists (e.g., orforglipron) aimed at improving global accessibility; multi-receptor agonists such as triple GLP-1/GIP/glucagon agonists (e.g., retatrutide, reportedly achieving 20–24% weight reduction) and dual GLP-1/glucagon agonists (e.g., survodutide, mazdutide) with potential benefits in metabolic-associated steatotic liver disease; novel dosing strategies via GLP-1/GIP combination agents (e.g., maridebart cafraglutide); amylin pathway agents (e.g., cagrilintide, amycretin); lean-mass-preserving agents (e.g., bimagrumab); and precision approaches for monogenic obesity (e.g., setmelanotide). The authors call for phenotype-stratified trials, long-term safety data, pediatric research, and equitable implementation. As a review, it does not present original trial data and is inherently subject to selection and interpretation bias.
Metabolism open · Mar 2026DOI ↗ Animal only
This review paper examines the preclinical and limited clinical evidence surrounding Body Protective Compound-157 (BPC-157), a synthetic pentadecapeptide derived from gastric proteins. The authors summarize experimental findings across a range of tissue types, noting that BPC-157 appears to support angiogenesis, collagen synthesis, fibroblast activity, and nitric oxide pathway modulation in animal models, with reported benefits to muscle, tendon, ligament, bone, and gastrointestinal healing. Anti-inflammatory effects, including reduced cytokine activity and improved microvascular integrity, as well as pain modulation via peripheral and dopaminergic mechanisms, are also described. The review notes that human research is limited to small pilot studies in musculoskeletal pain, interstitial cystitis, and intravenous administration contexts, with no major adverse effects reported. The authors acknowledge significant limitations: inconsistent preparation standards, lack of rigorous controlled trials, limited clinical validation, and ongoing regulatory restrictions. The paper concludes that BPC-157 represents a promising candidate for regenerative medicine but that robust clinical evidence is needed before therapeutic use can be recommended. As a narrative review drawing primarily on animal data, it does not establish efficacy in humans.
International journal of molecular sciences · Mar 2026DOI ↗ Review
This paper is a narrative review examining survodutide, a dual GLP-1 and glucagon receptor agonist, in the context of obesity, metabolic dysfunction-associated steatohepatitis (MASH), and related metabolic conditions including type 2 diabetes and cardiovascular disease. The authors summarize survodutide's proposed mechanism of action — encompassing appetite suppression, improved glucose metabolism, and increased energy expenditure — and compare its dual-agonist profile against single-target incretin-based therapies such as GLP-1 receptor agonists alone. The review synthesizes findings from early-phase clinical trials, which the authors report showed significant weight loss and improvements in metabolic markers. Safety and tolerability are also discussed, alongside broader cardiovascular and metabolic benefits suggested by preliminary data. The authors acknowledge that the evidence base remains limited, stressing that long-term safety, durability of effect, patient-specific responses, and cost-effectiveness have not yet been fully established. Ongoing and future trials are highlighted as essential for clarifying survodutide's clinical role. As a review article, this paper does not generate new primary data, and its conclusions are bounded by the early-stage evidence available at the time of writing.
Minerva endocrinology · Mar 2026DOI ↗ In vitro
This study addressed the growing global burden of obesity and type 2 diabetes by designing novel peptide-based triagonists that simultaneously activate three receptors: GLP-1R (glucagon-like peptide-1 receptor), GCGR (glucagon receptor), and GIPR (glucose-dependent insulinotropic polypeptide receptor). The researchers used computer-aided drug design, bioinformatics analyses, and molecular dynamics simulations to rationally identify key sequence determinants, optimal modification sites, and to understand how peptide "stapling" (a structural stabilization technique) affects alpha-helical stability and conformational rigidity. Based on these computational insights, 22 novel triagonist peptide structures were designed and synthesized. Their activity was evaluated in vitro using fluorescence membrane potential assays, with pharmacological balance assessed via a "balanced triagonism score" measuring consistency of activity across all three receptors. Most compounds showed highly balanced activity profiles. The lead compound, P2-L4, demonstrated low-nanomolar potency across all three receptor targets, with efficacy reported as comparable to existing incretin-based reference therapeutics. The study is limited to in vitro findings only, with no animal or human data reported. Further preclinical and clinical validation is required before any therapeutic conclusions can be drawn.
RSC medicinal chemistry · Mar 2026DOI ↗ 🧪 TrialInsufficient
Registered N/A interventional trial (not yet recruiting). The goal of this clinical trial is to assess whether adjunctive dental cleaning can enhance the effects of semaglutide in children with obesity. The main question\[s\] it aims to answer \[is/are\]: if dental cleaning will improve both oral health and metabolic outcomes beyond the effects of semaglutide alone. Participants will receive either dental cleaning and oral hygiene instruction or oral hygiene instruction alone.
ClinicalTrials.gov · Mar 2026View trial ↗ Moderate · human
This systematic review and meta-analysis evaluated the efficacy and safety of cagrisema (a fixed-ratio combination of the amylin analogue cagrilintide and the GLP-1 receptor agonist semaglutide) and cagrilintide monotherapy compared with semaglutide monotherapy for obesity management. Researchers searched five major databases and ClinicalTrials.gov, ultimately including three randomized controlled trials comprising 3,545 participants. Using a random-effects model, the study found that cagrisema produced statistically significantly greater reductions in percentage body weight (mean difference –7.47%, 95% CI: –10.58 to –4.36) and absolute body weight compared with semaglutide alone. Cagrisema also demonstrated superior improvements in glycemic markers, including fasting plasma glucose and HbA1c, and in BMI. Lipid parameters and safety profiles were reported as broadly comparable between groups. The authors concluded that cagrisema showed greater weight-loss efficacy and glycemic benefit than semaglutide, with an acceptable tolerability profile. Limitations include the small number of included trials (n=3), potential heterogeneity across trial designs, and the relatively short follow-up durations typical of early-phase RCTs in this therapeutic area.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ In vitro
This study presents the first comprehensive structure-activity relationship (SAR) analysis of SLU-PP-332, a synthetic agonist of estrogen-related receptors (ERRα and ERRγ) — nuclear receptors that regulate mitochondrial metabolism and exercise-responsive gene transcription. The researchers synthesized a library of SLU-PP-332 analogues and systematically varied core pharmacophoric elements, evaluating their effects using cell-based functional assays, downstream gene-expression profiling, and computational modeling (docking and molecular dynamics simulations). The study found that specific structural features of the SLU-PP-332 scaffold govern ERR potency, transcriptional efficacy, selectivity, ligand efficiency, solubility, and metabolic stability. While SLU-PP-332 remained a strong benchmark, certain analogues showed comparable or context-dependent transcriptional activity alongside improvements in ligand efficiency, solubility, or metabolic stability. Computational analyses helped explain how subtle chemical modifications influence receptor engagement and downstream signaling. Limitations include reliance on cell-based and in silico methods with no animal or human data reported. The work establishes design principles for next-generation ERR agonists and positions these compounds as potential exercise-mimetic therapeutics, though extensive preclinical and clinical validation remains to be done.
International journal of biological macromolecules · Mar 2026DOI ↗ Animal only
This review paper examines the potential therapeutic role of BPC 157 (a synthetic 15-amino-acid peptide derived from a gastric protein) in treating severe electrolyte disturbances, drawing on a collection of animal and in-vitro experiments. The paper covers four electrolyte scenarios: (1) hyperkalemia — where BPC 157 was reported to counteract KCl overdose effects including arrhythmias, hypertension, sphincter dysfunction, and mortality in rat models; (2) hypokalemia — where BPC 157 administration (both prophylactically and therapeutically) was reported to prevent fatal outcomes, ECG abnormalities, AV block, and skeletal muscle myoclonus in furosemide-treated rats; (3) hypermagnesemia — where BPC 157 appeared to alleviate muscle weakness, brain lesions, and secondary hyperkalemia in rats; and (4) lithium intoxication — where BPC 157 was reported to promote collateral vascular pathways and resolve multiorgan failure features. In-vitro experiments using HEK293 cells suggested BPC 157 can modulate membrane potential changes induced by electrolyte imbalances. Key limitations include reliance on animal and cell-based data with no human clinical trials reported, and the review format limits independent assessment of individual study methodologies.
Current neuropharmacology · Mar 2026DOI ↗ Review
This narrative review synthesizes the existing literature on the metabolic benefits of GLP-1 receptor agonists and dual GLP-1/GIP receptor agonists in individuals with overweight or obesity. The authors examine evidence supporting these agents' effectiveness for weight reduction and glycemic control, as well as their purported direct effects on multiple organ systems beyond glucose regulation. The review also explores the medium- to long-term implications for metabolic disease outcomes, including considerations of safety and cost-effectiveness with prolonged use. The authors conclude that GLP-1-based therapies show promise for both the improvement and prevention of metabolic disease, while noting that longer-duration studies are needed to broaden approved indications and confirm the safety profile of these agents. As a narrative review, the paper is subject to inherent limitations including potential selection bias in the literature chosen, the absence of a systematic search protocol or meta-analytic pooling, and reliance on the quality and duration of the underlying primary studies, which the authors themselves acknowledge are insufficiently long in many cases.
Healthcare (Basel, Switzerland) · Mar 2026DOI ↗ Animal only
This review paper proposes cytoprotection as a unifying therapeutic framework to address what the authors call the "hemorrhage-thrombosis paradox" — the clinical challenge that hemorrhage and thrombosis can coexist as phase-dependent manifestations of vascular dysregulation. The paper centers on BPC 157, a stable synthetic gastric pentadecapeptide, which the authors argue can simultaneously counteract both hemorrhage and thrombosis in rodent models without directly interfering with the coagulation cascade (as assessed by aggregometry and thromboelastometry). The review synthesizes preclinical and conceptual evidence to argue that BPC 157 achieves this bidirectional vascular regulation through preservation of endothelial integrity, normalization of microcirculation, modulation of the nitric oxide system, and recruitment of collateral adaptive pathways. The authors contrast this proposed "full cytoprotection" with the "partial cytoprotection" of conventional agents such as anticoagulants, antiplatelet drugs, fibrinolytics, beta blockers, calcium channel blockers, and statins, which they contend act in isolated or unidirectional ways. The paper also discusses applications in wound healing, arrhythmia control, and normalization of Virchow's triad. Notably, the authors explicitly acknowledge that findings are predominantly preclinical and that clinical validation in humans remains necessary.
Pharmaceuticals (Basel, Switzerland) · Mar 2026DOI ↗ Animal only
This animal study investigated whether Growth Hormone-Releasing Peptide-6 (GHRP-6), a GH secretagogue hexapeptide, could reduce cardiac damage following myocardial infarction. Using a permanent left coronary artery ligation model in rats (a non-reperfusion model), researchers divided animals into three groups: sham-operated controls, infarcted rats treated with saline, and infarcted rats treated with GHRP-6. Treatment began post-surgery and continued for seven days. Outcomes were assessed via echocardiography and histology on day seven. A separate cohort of twelve healthy rats was used for mitochondrial proteomic analysis six hours after compound administration. The study found that, compared to the saline-treated infarcted group, GHRP-6-treated rats showed reduced myocardial tissue loss, less interstitial fibrosis and scarring, and improved left ventricular function. Proteomic data suggested that potential mechanisms may include upregulation of fatty acid beta-oxidation, apoptosis-prevention pathways, antioxidant defenses, and mitochondrial metabolic reprogramming. Key limitations include the exclusive use of an animal model, a short seven-day observation window, a small sample size, and the mechanistic proteomic findings being derived from healthy rather than infarcted animals. No human data were generated.
Pharmaceuticals (Basel, Switzerland) · Mar 2026DOI ↗ 🧪 TrialInsufficient
Registered Phase 2 interventional trial (recruiting). Phase 2, multicenter, randomized, double-blind, placebo-controlled study evaluating once-weekly subcutaneous retatrutide (LY3437943) at multiple maintenance dose levels versus placebo in adults with obesity or overweight with weight-related comorbidities (without type 2 diabetes), alongside standardized diet and physical activity counseling.
ClinicalTrials.gov · Mar 2026View trial ↗ Moderate · human
This retrospective cohort study used electronic health records from a large health system in Ohio and Florida (January 2021–June 2025) to examine real-world obesity treatment patterns and weight changes among adults who discontinued injectable semaglutide or tirzepatide within 3–12 months of initiation. A total of 7,938 patients (mean age ~56 years; ~64% female) were included. The study found that within one year of discontinuation, roughly 19.6% restarted the same medication and 35.2% received an alternative obesity treatment (most commonly another medication). Patients treated for obesity lost a mean of 8.4% of body weight before discontinuation, while those treated for type 2 diabetes lost 4.4%. In the year following discontinuation, the average weight change was modest (+0.5% for obesity indication; −1.3% for T2D indication), but with considerable individual-level variability—meaning some patients regained weight substantially while others did not. Key limitations include the retrospective, observational design (precluding causal inference), potential confounding by unmeasured factors, and restriction to a single health system in two U.S. states, which may limit generalizability.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Animal only
This animal study investigated whether MOTS-c, a 16-amino acid mitochondrial-derived peptide, influences adrenal gland physiology in adult male Wistar rats. Sixteen rats received either continuous subcutaneous MOTS-c or saline for 24 hours via micro-osmotic pumps. The researchers used qRT-PCR, immunohistochemistry, ELISA, and RNA sequencing to assess adrenal tissue responses. The study first confirmed that endogenous MOTS-c expression was higher in the zona fasciculata/reticularis compared to the zona glomerulosa. MOTS-c treatment did not alter classical steroidogenic gene expression or circulating corticosterone and aldosterone levels. However, RNA sequencing identified 39 differentially expressed genes, most notably a 4.3-fold upregulation of the purinergic receptor P2ry4. The authors interpreted these findings as evidence that MOTS-c "primes" adrenocortical cells for steroidogenic responsiveness—via calcium signaling, lipid metabolism modulation, stress-response protein downregulation, and mitophagy inhibition—without directly stimulating basal hormone synthesis. Key limitations include the exclusive use of male rats, the short 24-hour treatment window, small sample size (n=16), and the absence of functional stimulation challenges (e.g., ACTH) to test the proposed "readiness" hypothesis.
Folia histochemica et cytobiologica · Mar 2026DOI ↗ 🧪 TrialInsufficient
Registered Phase 1/Phase 2 interventional trial (recruiting). The purpose of this study is to: * evaluate the safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of single ascending doses of ALN-2232 in patients with obesity * evaluate the safety, tolerability, efficacy, PK, and PD of multiple doses of ALN-2232 in patients with obesity * evaluate the safety, tolerability, efficacy, PK, and PD of multiple doses of ALN-2232 co-initiated with tirzepatide in patients with obesity
ClinicalTrials.gov · Mar 2026View trial ↗ Review
This narrative review compares two incretin-based therapies — semaglutide, a selective GLP-1 receptor agonist, and tirzepatide, a dual GIP/GLP-1 receptor agonist — across their mechanisms of action, clinical efficacy, therapeutic indications, and cardiovascular/renal evidence. The authors describe semaglutide as having a well-established clinical profile with demonstrated benefits in glycaemic control, body weight reduction, and cardiovascular and renal outcomes. Tirzepatide is presented as a newer agent offering superior weight loss and improvements in insulin sensitivity, with an expanding range of therapeutic indications, though the authors note its cardiovascular outcomes evidence is less mature than that of semaglutide. The review emphasizes that despite shared benefits in reducing HbA1c and body weight, the two molecules differ meaningfully in their pharmacological mechanisms and evidence bases, requiring individualized clinical decision-making. The authors frame both agents within a broader "incretin revolution" relevant to cardio-reno-metabolic prevention. As a narrative review, this paper synthesizes existing literature rather than generating new primary data, and therefore does not provide independent experimental evidence to confirm or quantify any specific clinical claims.
European heart journal supplements : journal of the European Society of Cardiology · Mar 2026DOI ↗ Animal only
This study examined the effects of graviola (Annona muricata L.) oil extract (GOE) supplemented at three doses (200, 400, and 600 mg/kg feed) on growth performance and circadian rhythm profiles of several biomarkers in 48 male Anatolian Merino lambs over a 60-day feeding trial. Blood samples were collected at four time points across the day (07:00, 13:00, 19:00, and 01:00) on multiple study days to capture circadian variation. Measured biomarkers included Apelin (an adipokine), cardiac troponin I (cTnI), the circadian clock protein BMAL1, the mitochondria-derived peptide MOTS-c, and brown adipose mitochondrial carrier protein 1 (BMCP1), all assessed via ELISA. The 400 mg/kg dose was associated with the greatest linear improvement in live weight gain and with modulation of BMAL1, MOTS-c, and BMCP1 peaking at 19:00. The 600 mg/kg dose showed the most favorable results for Apelin and cTnI at certain time points. Limitations include the exclusive use of a single animal species, a relatively small sample size, lack of human relevance, and the observational nature of biomarker interpretation within a non-randomized animal production context.
BMC veterinary research · Mar 2026DOI ↗ Moderate · human
This meta-analysis pooled data from five randomised controlled trials to evaluate the efficacy and safety of mazdutide — a dual GLP-1 and glucagon receptor agonist — for weight management in non-diabetic adults with overweight or obesity. Searches were conducted across Cochrane Library, PubMed, Google Scholar, and ClinicalTrials.gov, and analyses were performed using random-effects models in RevMan 5.4. The pooled results reported by the study authors indicate that mazdutide was associated with significant reductions in percentage body weight (mean difference –12.42%), absolute body weight (–9.76 kg), and waist circumference (–7.98 cm) compared with control conditions. Secondary cardiometabolic outcomes — including systolic blood pressure (–7.68 mmHg), total cholesterol (–0.57 mmol/L), and LDL cholesterol (–0.37 mmol/L) — also showed reductions. Adverse events were slightly more frequent in the mazdutide groups (RR = 1.12), described as mild to moderate. A dose-wise meta-regression suggested a significant dose-dependent relationship. The authors acknowledge that findings are constrained by the small number of included trials (n = 5), which limits the robustness and generalisability of conclusions.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Review
This paper is a narrative review examining the clinical evidence on retatrutide (LY3437943), a novel triple receptor agonist targeting the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). The authors conducted an electronic literature search across Scopus, PubMed/MEDLINE, and Google Scholar to synthesize available findings. According to the review, studies in people with type 2 diabetes mellitus (T2DM) reported reductions in HbA1c of up to 2.16% and fasting glucose reductions of up to 69.1 mg/dL, alongside weight loss of up to 16.94%. In individuals with overweight or obesity (without T2DM), weight loss reached up to 26.56% (approximately 24.15 kg). Additional findings included reductions in BMI, waist circumference, and systolic blood pressure in those with T2DM and overweight/obesity, as well as a relative liver fat reduction of up to 86% in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD). The most commonly reported adverse events were mild-to-moderate gastrointestinal symptoms, particularly at higher doses. The authors conclude that retatrutide's effects on glycemic control, weight, and potential pleiotropic benefits warrant further investigation through larger, longer-duration trials.
Expert review of clinical pharmacology · Mar 2026DOI ↗ 🧪 TrialInsufficient
Registered Phase 4 interventional trial (not yet recruiting). SHAPE-ENDO is a single-center, open-label, pilot randomized clinical trial conducted at Hospital Universitari de Bellvitge in Barcelona, Spain. The study will evaluate the feasibility, safety, and acceptability of comparing two treatment strategies in women with atypical endometrial hyperplasia/endometrial intraepithelial neoplasia or low-risk endometrioid endometrial cancer and grade III obesity, defined as BMI ≥40 kg/m². Eligible participants will be randomized in a 1:1 ratio to one of two arms. The control arm will undergo standa
ClinicalTrials.gov · Mar 2026View trial ↗