Review
This review article examines the evolving landscape of glucagon-like peptide-1 (GLP-1)-based therapies for obesity management. The authors describe how obesity, a major risk factor for type 2 diabetes and cardiovascular disease, often resists traditional lifestyle interventions, motivating the development of more targeted pharmacological approaches. The review focuses on incretin mimetics — drugs that mimic nutrient-stimulated hormones — which act on G-protein-coupled receptors including GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptors. Specific agents highlighted include semaglutide and tirzepatide, as well as emerging multiagonist compounds such as GLP-1/glucagon and GIP/GLP-1/glucagon receptor co-agonists. The authors argue that glucagon receptor activation in particular represents a meaningful frontier in the field. The review surveys clinical efficacy data, neuroendocrine mechanisms, and signaling pathways underlying these therapies, while also outlining remaining challenges and future research directions. As a narrative review, it synthesizes existing literature rather than presenting original trial data, and does not conduct a formal meta-analysis. Its conclusions are therefore dependent on the quality and selection of the underlying primary studies reviewed.
Endocrinology and metabolism (Seoul, Korea) · Apr 2024DOI ↗ Animal only
This animal study investigated whether AMP-activated protein kinase (AMPK) in the central nucleus of the amygdala (CeA) serves as an intracellular signaling mediator linking metabolic cues—ghrelin, fasting, and glucoprivation—to food intake regulation. Male Wistar rats were surgically implanted with cannulas in the CeA and received intra-CeA injections of various modulators, including glucose, 2-deoxy-D-glucose (2DG), ghrelin, and Melanotan II (MTII). The study measured AMPK phosphorylation at Thr172 (AMPKThr172) alongside food intake and body weight. Key findings attributed to the study include: fasting increased and refeeding reduced CeA AMPKThr172; intra-CeA glucose reduced food intake while 2DG (a glucoprivation inducer) increased food intake and blood glucose with modest AMPKThr172 elevation; intra-CeA ghrelin increased both food intake and AMPKThr172; and chronic intra-CeA MTII injection reduced body mass and food intake over seven days alongside a slight reduction in AMPKThr172. Limitations include use of a single rodent model, small and unspecified sample sizes per group, and the inability to establish direct causality between AMPK activation and feeding behavior. No human data were collected.
Molecular and cellular endocrinology · Apr 2024DOI ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (completed). The purpose of this study is to investigate the efficacy and safety of retatrutide compared with placebo in participants with Type 2 Diabetes and inadequate glycemic control. The study will last about 11 months and may include up to 11 visits.
ClinicalTrials.gov · Apr 2024View trial ↗ Animal only
This review paper examines the proposed mechanisms underlying the wide-ranging (pleiotropic) biological effects of BPC 157, a synthetic 15-amino-acid peptide described as stable in human gastric juice. The authors attempt to frame BPC 157's observed effects within classical neurotransmitter criteria — including production, release, receptor interaction, and clearance — while acknowledging that direct conclusive evidence meeting these criteria is lacking. Instead, the paper compiles a network of interconnected preclinical evidence suggesting that BPC 157 may counteract disturbances across multiple neurotransmitter systems, including dopamine, serotonin, glutamate, GABA, adrenaline/noradrenaline, acetylcholine, and the nitric oxide (NO) system. The paper also discusses potential receptor interactions (e.g., VEGF and growth hormone receptors) and observations related to nerve-muscle and nerve-nerve relationships in various experimental models. The authors draw parallels between BPC 157's activity and gasotransmitter behavior. A key limitation explicitly noted by the authors is the absence of direct human clinical trial data; the evidence base relies predominantly on animal and in vitro studies. This paper does not establish clinical efficacy or safety in humans.
Pharmaceuticals (Basel, Switzerland) · Apr 2024DOI ↗ Animal only
This paper describes the preclinical pharmacological profiling and biomarker-guided selection process used to identify survodutide (BI 456906) as a clinical development candidate from a library of 19 dual glucagon receptor (GCGR)/GLP-1R agonists. Researchers assessed receptor potency using cAMP assays in CHO-K1 cells expressing human GCGR and GLP-1R, as well as in insulinoma (MIN6) cells and rat primary hepatocytes for endogenous receptor activity. In vivo target engagement was evaluated in lean mice using oral glucose tolerance tests (GLP-1R biomarker) and plasma FGF21 and liver NNMT mRNA expression (GCGR biomarkers). Efficacy was further tested in diet-induced obese (DIO) mice for body weight reduction and in diabetic db/db mice for glucose lowering. A strong correlation was found between in vitro and in vivo GCGR and GLP-1R biomarkers, enabling candidate ranking. Survodutide demonstrated balanced dual agonism, producing greater body weight reduction than selective GLP-1R agonists while maintaining comparable antidiabetic effects. Key limitations include that all efficacy data are from rodent models, and human pharmacological profiling is not reported in this paper. Survodutide is now in Phase 3 clinical trials for obesity.
Diabetes, obesity & metabolism · Apr 2024DOI ↗ Animal only
This rat study investigated whether larazotide acetate (LA), a tight junction regulator that blocks zonulin receptors in the intestinal epithelium, could reduce intestinal barrier dysfunction and bacterial translocation in an experimentally induced acute pancreatitis (AP) model. Thirty-two male Sprague-Dawley rats were divided into four groups (control, larazotide-only, AP, and AP + larazotide). AP was induced via intraperitoneal L-Arginine injections, and LA was administered orally for seven days prior to AP induction. Intestinal permeability was assessed using FITC-Dextran, bacterial translocation was evaluated by culturing samples from liver, mesentery, and spleen, and intestinal histopathology including zonulin-1 (ZO-1) immunoreactivity was analyzed. The study found that, compared to the AP-only group, the AP + LA group showed significantly reduced intestinal damage scores, lower serum FITC-Dextran levels, decreased ZO-1 immunoreactivity, and a lower frequency of bacterial translocation. Key limitations include the exclusive use of an animal model, a small sample size, a single AP-induction method (L-Arginine), and a prophylactic rather than therapeutic administration design, which may limit clinical translatability.
Digestive diseases and sciences · Mar 2024DOI ↗ Review
This review paper examines the landscape of FDA-approved peptide therapeutics, tracing the field's evolution from the discovery of insulin in 1921 to approximately 100 subsequently authorized peptide drugs. The author focuses on six key peptide classes: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) analogues for diabetes management, growth-hormone-releasing hormone (GHRH) analogues, cholecystokinin (CCK) analogues, adrenocorticotropic hormone (ACTH) analogues, and α-melanocyte-stimulating hormone (α-MSH) analogues. For each class, the review describes the native peptide's biological structure and mechanism of action, the medicinal chemistry strategies used to engineer synthetic analogues (such as modifications that extend half-life and reduce dosing frequency), the developmental and regulatory journey toward FDA approval, and known adverse effects. The paper highlights how targeted chemical modifications—including structural stabilization techniques—have improved the therapeutic utility of naturally derived peptides beyond their endogenous counterparts. Limitations include those inherent to any narrative review: no systematic search methodology or meta-analytic statistics are reported, and no original clinical or experimental data are generated. The work serves primarily as an educational synthesis of existing literature.
Biomolecules · Feb 2024DOI ↗ In vitro
This study explores novel peptide stapling strategies inspired by natural product motifs found in fungal toxins (amatoxins, phallotoxins) and the alkaloid staurosporine. The researchers developed a chemical method using a 5-hydroxypyrroloindoline building block that can react with either a cysteine thiol (forming a tryptathionine staple) or a tryptophan indole (forming a 2,2'-bis-indole staple) to create constrained macrocyclic peptide structures. The authors applied these two stapling approaches to α-melanocyte-stimulating hormone (α-MSH), using the Melanotan-II scaffold as a model, with careful protecting group strategies to achieve chemoselectivity between the two staple types. Both classes of stapled peptides were evaluated for binding affinity at the melanocortin receptor, and the study reports that both series achieved nanomolar inhibition constants (Ki values), with at least one compound reaching sub-nanomolar Ki. Limitations include that all work is conducted in vitro (binding assays and synthetic chemistry), with no cell-based functional data, animal studies, or human data reported. The study is primarily a proof-of-concept for expanding the chemical toolbox of peptide stapling using underexplored natural product-derived cross-links.
Chemistry (Weinheim an der Bergstrasse, Germany) · Feb 2024DOI ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (active not recruiting). The purpose of this study is to investigate the efficacy and safety of retatrutide compared with semaglutide in participants with Type 2 Diabetes and inadequate glycemic control with metformin with or without sodium-glucose cotransporter-2 inhibitor (SGLT2i). The study will last about 26 months and may include up to 24 visits.
ClinicalTrials.gov · Feb 2024View trial ↗ Preclinical
This study developed and validated a simultaneous analytical method using ultra-high-performance liquid chromatography coupled with high-resolution Orbitrap mass spectrometry (UHPLC-Q-Exactive MS/MS) to quantify TB-500 (Ac-LKKTETQ), a synthetic peptide derived from the active site of thymosin β4 (Tβ4), alongside its metabolites. Metabolism was studied in human serum, multiple in-vitro enzyme systems, and rat urine samples following TB-500 administration. Researchers synthesized authentic standards of the metabolites to enable structural identification. Key findings included that Ac-LK was the predominant short-term metabolite (0–6 hours), while Ac-LKK was detectable as a longer-term metabolite up to 72 hours. In fibroblast cell culture experiments, neither TB-500 nor its metabolites demonstrated cytotoxicity. Notably, among all compounds tested, only the metabolite Ac-LKKTE showed statistically significant wound-healing activity compared to controls, leading the authors to suggest that previously reported wound-healing effects attributed to TB-500 in the literature may actually be mediated by this metabolite rather than the parent peptide. Limitations include that biological activity testing was confined to cell-based assays, and no human pharmacokinetic or efficacy data were generated.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences · Feb 2024DOI ↗ Animal only
This study investigated whether hexarelin — a synthetic peptide ligand targeting the CD36 receptor — could reduce the hyper-inflammatory response associated with severe SARS-CoV-2 infection. Using the K18-hACE2 transgenic mouse model, which expresses the human ACE2 receptor and is widely used to study COVID-19 pathology, the researchers examined how SARS-CoV-2 infection drives alveolar macrophages toward a pro-inflammatory phenotype and whether CD36 modulation could interrupt this process. The study found that CD36 signaling appears to play a regulatory role in macrophage-driven cytokine overproduction — the so-called "cytokine storm" — and that hexarelin treatment showed potential for blunting this response, thereby potentially limiting progression to acute respiratory distress syndrome (ARDS). The study is limited by its reliance on an animal model, meaning results may not translate directly to human patients. The transgenic mouse system, while a useful proxy for human COVID-19, does not fully recapitulate human immunological complexity. No clinical data in humans were presented. The authors acknowledge that ARDS from SARS-CoV-2 remains an unmet therapeutic need and position hexarelin as a candidate for further investigation.
Frontiers in pharmacology · Feb 2024DOI ↗ Moderate · human
This phase 2 randomised, double-blind, placebo-controlled trial investigated the safety, tolerability, and efficacy of survodutide (BI 456906), a glucagon receptor and GLP-1 receptor dual agonist, for weight management in adults with obesity but without diabetes. Across 43 centres in 12 countries, 386 participants (BMI ≥27 kg/m²) were assigned to one of four subcutaneous survodutide doses or placebo, administered once weekly for 46 weeks. The primary endpoint was percentage change in bodyweight from baseline to week 46. The study found dose-dependent reductions in bodyweight across all survodutide groups compared to placebo, ranging from approximately -6.2% to -14.9% versus -2.8% for placebo. Gastrointestinal adverse events were the most common side effects, occurring in 75% of survodutide recipients compared to 42% of placebo recipients. Notably, only about 60% of participants completed the full 46-week treatment period, and the study was not powered to establish definitive efficacy or compare doses head-to-head. As an industry-funded phase 2 dose-finding trial, these results are considered preliminary and intended to inform larger confirmatory studies.
The lancet. Diabetes & endocrinology · Feb 2024DOI ↗ Animal only
This animal study investigated how the melanocortin receptor agonist Melanotan II (MTII) affects brain activity in prairie voles, with a focus on whether its effects depend on social context and the oxytocin system. Researchers administered MTII to male and female prairie voles either before social interactions or in non-social conditions, then used Fos expression (a marker of neuronal activation) to map brain activity. In non-social contexts, MTII activated only the hypothalamic paraventricular nucleus (PVN), the brain's primary site of oxytocin production. However, when MTII was given before social interactions, it selectively increased oxytocin-dependent activation in the nucleus accumbens — a region critical for social learning and reward. The authors propose this mechanism may explain how MTII accelerates partner preference formation (a model of social bonding) seen in earlier studies. The study frames these findings as supportive of a treatment model where endogenous oxytocin is pharmacologically stimulated during behavioral therapy, rather than via chronic exogenous oxytocin supplementation. Limitations include the use of a single animal species, an animal-only design, and the inherent challenges of translating prairie vole social bonding models to human psychiatric conditions such as autism.
Neuropharmacology · Jan 2024DOI ↗ Animal only
This preclinical study investigated SLU-PP-332, a synthetic agonist targeting estrogen-related receptors (ERRα, ERRβ, and ERRγ), as a potential pharmacological "exercise mimetic" for treating obesity and metabolic syndrome. Researchers administered the compound to two mouse models — diet-induced obese mice and genetically obese (ob/ob) mice — and measured a range of metabolic outcomes. The study found that SLU-PP-332 administration was associated with increased whole-body energy expenditure and enhanced fatty acid oxidation, effects the authors liken to those induced by aerobic exercise. These changes were accompanied by reductions in fat mass accumulation. The compound also appeared to improve insulin sensitivity in the metabolic syndrome models. The study's primary limitation is that all experiments were conducted exclusively in mouse models, meaning the findings cannot be directly extrapolated to humans. Differences in ERR biology, pharmacokinetics, and disease physiology between rodents and humans represent significant translational barriers. The authors conclude that pharmacological ERR activation warrants further investigation as a potential strategy for metabolic disease treatment.
The Journal of pharmacology and experimental therapeutics · Jan 2024DOI ↗ Limited · human
This study developed and validated a unified chromatographic-mass spectrometric (LC-MS) method for detecting a broad range of prohibited peptide drugs (molecular mass 2–10 kDa) in doping control urine samples. The target analytes spanned five categories: insulins (human and animal-derived, including several analogues and a metabolite), growth hormone-releasing hormones (GHRHs) and their metabolites, insulin-like growth factors (IGF variants), synacthen, gonadorelin, and mechano growth factors. A key goal was simplifying sample preparation by consolidating what are traditionally separate, complex analytical workflows into a single procedure, controlled by five internal standards—one per peptide category. The method was validated as an initial testing procedure and shown to meet nearly all World Anti-Doping Agency (WADA) Minimum Required Performance Levels (MRPLs). As a proof of principle, the method was applied to authentic post-administration urine samples from human subjects dosed with insulins and gonadorelin, demonstrating real-world detection capability. Limitations include that human subject data are limited to proof-of-concept post-administration samples rather than a controlled efficacy or pharmacological trial, and the study's primary focus is analytical method development rather than clinical outcomes.
Journal of mass spectrometry : JMS · Jan 2024DOI ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (completed). This is a multicenter, randomized, Open-label Phase 3 clinical study comparing the efficacy and safety of IBI362 6 mg OW versus Semalgutide 1 mg OW in obese(BMI≥28kg/m2) early T2D subjects. Subjects will be randomly assigned to IBI362 6 mg and Semalgutide 1 mg groups for 32 weeks (active-controlled treatment period). In the extension period, participants originally on mazdutide were assigned to continue for an additional 24 weeks with mazdutide 9 mg or 6 mg based on whether they achieved the weight-loss target. All study treatment will be ad
ClinicalTrials.gov · Dec 2023View trial ↗ Review
This review article summarizes discussions from a round table held at the European Society for Sexual Medicine (ESSM) meeting in Rotterdam (February 2023), where leading experts addressed the diagnosis and treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. The authors note that HSDD is the most prevalent female sexual disorder, reported by approximately 28% of the estimated 40% of premenopausal women experiencing sexual dysfunction. The review covers the multifactorial nature of HSDD, encompassing biological, psychological, and sociocultural dimensions—including depression, sexual abuse history, gender-based "pleasure gaps," and structural inequalities. Regarding pharmacotherapy, the authors note that flibanserin and bremelanotide are the only FDA-approved treatments in the USA, while no medications are approved in Europe; compounds such as Lybrido, Lybridos, and Lorexys remain under development. The review reports that evidence supports combining pharmacological and psychosocial approaches, though clinician opinion remains divided. It also highlights that some women express a clear desire for access to drug-based options. A key limitation is that this article is expert opinion and narrative review rather than a systematic review or primary study, limiting the strength of its evidence base.
Pharmacology · Dec 2023DOI ↗ Moderate · human
This Phase II randomised controlled trial evaluated survodutide (BI 456906), a dual glucagon receptor/GLP-1 receptor agonist, across six dose groups compared with placebo and open-label semaglutide (1.0 mg once weekly) in 413 adults with type 2 diabetes on metformin background therapy. Over 16 weeks, survodutide produced dose-dependent reductions in HbA1c and bodyweight. Higher dose groups achieved HbA1c reductions of approximately 17–19 mmol/mol (~1.6–1.7%), broadly comparable to semaglutide (~16 mmol/mol, ~1.5%), while lower doses showed smaller reductions. Bodyweight decreased dose-dependently, with the highest-dose groups producing greater reductions (up to ~8.7%) than semaglutide (~5.3%). Adverse events, predominantly gastrointestinal, were reported in ~78% of survodutide-treated participants versus ~52% in both the placebo and semaglutide groups. Limitations include the relatively short 16-week treatment duration, the open-label (non-blinded) design of the semaglutide comparator arm, and the Phase II exploratory nature of the trial, which was not powered for head-to-head superiority conclusions. The trial was funded by Boehringer Ingelheim.
Diabetologia · Dec 2023DOI ↗ In vitro
This study used all-atom molecular dynamics (MD) simulations, complemented by Fourier transform infrared (FTIR) spectroscopy, to investigate how two permeability enhancers (PEs) — sodium caprate and SNAC (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate) — interact with four peptide drugs (octreotide, hexarelin, degarelix, and insulin) in the presence of taurocholate, an intestinal bile salt. The simulations revealed that the two PEs had distinct, peptide-dependent effects: they tended to promote release of more hydrophobic peptides while inhibiting release of more water-soluble ones. At lower peptide concentrations, peptide–peptide interactions decreased while interactions with PEs and taurocholate increased. Introducing all components together produced dynamic mixed aggregates with reduced peptide–peptide hydrogen bonding compared to peptide-only systems. FTIR analysis of insulin showed that SNAC increased β-sheet formation, while sodium caprate favored α-helical and random-coil structures. The authors suggest these molecular-level insights could guide the rational design of PE-based oral peptide formulations. Key limitations include the exclusive use of computational and in vitro/spectroscopic methods, with no cell-based, animal, or human data reported.
Nanoscale · Dec 2023DOI ↗ Review
This comprehensive review examines Hypoactive Sexual Desire Disorder (HSDD) in women, covering its etiology, diagnosis, treatment, and societal implications. The authors explore biological contributors — including hormonal fluctuations and neurotransmitter imbalances — alongside psychological factors such as stress, body image, and relationship dynamics, and sociocultural influences including media and cultural norms. Diagnostic criteria from DSM-5 and self-report assessment tools are reviewed to aid accurate identification and differentiation from other sexual disorders. The review surveys a broad spectrum of treatment options: non-pharmacological approaches (cognitive-behavioral therapy, sex therapy, couples therapy), pharmacological interventions (hormone therapy, SSRIs), and novel agents such as flibanserin and bremelanotide, as well as integrative strategies combining psychotherapy with lifestyle modification. The authors also address ongoing controversies, including lack of diagnostic consensus, concerns about medicalizing female sexuality, and ethical questions around pharmaceutical promotion. Future research directions highlighted include advances in neurobiology, personalized medicine, long-term outcome studies, and destigmatization efforts. As a narrative review, this paper synthesizes existing literature rather than generating new primary data, and is therefore subject to the limitations of selective source inclusion and potential author bias.