Insufficient
SYNCHRONIZE-CVOT is a phase 3, randomized, double-blind, placebo-controlled, event-driven cardiovascular (CV) outcomes trial evaluating survodutide — a dual glucagon and GLP-1 receptor agonist administered subcutaneously once weekly — in adults with obesity or overweight (BMI ≥27 kg/m²) who also have established CV disease, chronic kidney disease, and/or at least two weight-related complications or CV risk factors. The primary endpoint is time to first occurrence of a 5-point major adverse cardiovascular event (MACE) composite. The trial targets enrollment of 4,935 participants globally and is currently in the recruitment phase (NCT06077864). The paper describes the scientific rationale — that dual glucagon/GLP-1 receptor agonism may produce greater weight reduction than GLP-1 agonism alone — and outlines the trial design in detail. As a design/rationale publication, no efficacy or safety outcomes are yet available. Key limitations at this stage include the absence of results and the event-driven nature meaning the timeline is uncertain. This trial will be the first to formally assess CV safety and potential efficacy of survodutide in a high-risk obesity population.
JACC. Heart failure · Oct 2024DOI ↗ Animal only
This animal study investigated whether two synthetic analogs of the ACTH(4-10) peptide fragment — Semax (ACTH(4-7)-Pro-Gly-Pro) and Melanotan II (MTII), a melanocortin receptor agonist — possess antidepressant-like and antistress properties in a chronic unpredictable stress (CUS) rat model of depression. Male adult Sprague-Dawley rats were subjected to CUS and received daily intraperitoneal injections of either saline or a low dose of Semax or MTII. Outcomes assessed included body weight, hedonic status via the sucrose preference test, adrenal gland weight, hippocampal BDNF levels, and immobility in the forced swim test. The study found that both Semax and MTII reversed or substantially reduced CUS-induced anhedonia, suppressed body weight gain, adrenal hypertrophy, and decreased hippocampal BDNF levels. Neither the CUS procedure nor the peptide treatments produced significant effects on immobility in the forced swim test. The authors concluded that systemically administered ACTH(4-10) analogs may have therapeutic potential for depression and stress-related conditions. Key limitations include the exclusive use of male rats, an animal-only design with no human data, and restriction to a single dose level.
European journal of pharmacology · Oct 2024DOI ↗ Animal only
This study investigated whether the naturally occurring copper-binding peptide GHK-Cu (glycyl-L-histidyl-L-lysine copper complex) could reduce Alzheimer's disease (AD)-related pathology in a transgenic mouse model. Male and female 5xFAD mice — a well-established preclinical model of AD — were treated with intranasal GHK-Cu three times per week from 4 to 7 months of age, with a C57BL/6J background strain as context. The researchers assessed behavioral outcomes, amyloid plaque burden, and neuroinflammation markers. The study found that treated mice showed delayed cognitive impairment compared to untreated controls, along with reductions in amyloid plaques and lower levels of MCP1-associated inflammation in the frontal cortex and hippocampus. The authors suggest these findings justify further investigation of GHK-Cu as a potential AD therapeutic. Key limitations include the exclusively preclinical (animal) nature of the work — results in transgenic mouse models do not reliably predict outcomes in humans — and the fact that 5xFAD mice represent an aggressive, artificially accelerated form of amyloid pathology that may not fully reflect the complexity of human AD.
Aging pathobiology and therapeutics · Sep 2024DOI ↗ Insufficient
This forensic laboratory study describes the analytical challenges encountered when identifying Melanotan II — a synthetic peptide informally nicknamed the "Barbie drug" — in suspected illicit drug samples submitted for analysis. Researchers used HPLC-DAD, UHPLC-TOF-MS, and UPLC-MS/MS to characterize a powder found in pharmaceutical-appearing vials labeled "Melanotan II." Standard library searches via HPLC-DAD yielded no match, partly because the UV spectrum for Melanotan II was not available in the reference library at the time. Mass spectrometric identification was further complicated by the peptide's relatively high molecular weight (~1024 Da), which exceeded the typical detection ceiling of instruments configured for classical small-molecule drugs of abuse, and by the compound's multi-charged ionization behavior. Using a reference standard, the team ultimately confirmed the identity of Melanotan II and estimated a purity of approximately 30%. The study highlights that Melanotan II is not approved for market use due to safety concerns and is sold illicitly primarily for skin tanning. The authors suggest that the significant analytical hurdles involved in detecting this peptide may partly explain its growing presence on the illicit market. This study is a descriptive forensic case report with no clinical outcome data or human subject testing.
Journal of forensic sciences · Sep 2024DOI ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (completed). The main purpose of this study is to demonstrate that when participants with moderate to severe plaque psoriasis and obesity or overweight in the presence of at least 1 weight-related comorbid condition receive ixekizumab and tirzepatide concomitantly administered, participants see improvement in their psoriasis and achieve weight reduction compared to when receiving ixekizumab. Participation in this study includes up to 12 visits and could last up to 61 weeks including screening, open label treatment period, and post-treatment follow-up per
ClinicalTrials.gov · Sep 2024View trial ↗ Review
This review article provides a comprehensive overview of approved and emerging hormone-based anti-obesity medications (AOMs), situating them within the broader context of obesity as a complex, chronic, global disease. The authors summarize the current regulatory landscape, noting that the GLP-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide have received FDA and EMA approval for weight management. The review also covers pipeline agents, including oral GLP-1RAs (semaglutide, danuglipron, orforglipron), the amylin receptor agonist cagrilintide (alone and in combination with semaglutide), and dual agonists such as tirzepatide (GIP/GLP-1), survodutide, mazdutide, and pemvidutide (GLP-1R/GCGR). The authors highlight tirzepatide's placebo-subtracted weight reduction of 17.8% in a 72-week RCT and retatrutide's (a GLP-1R/GCGR/GIPR tri-agonist) placebo-subtracted reduction of 22.1% in a 48-week phase-II trial. The review cautions that long-term safety and cardiovascular outcome data for many of these agents remain incomplete. As a narrative review, it does not conduct original research or meta-analysis, and conclusions are limited by the quality and heterogeneity of the underlying primary studies it synthesizes.
Indian journal of endocrinology and metabolism · Sep 2024DOI ↗ Moderate · human
This systematic review and meta-analysis examined the weight-loss efficacy and safety of cagrilintide (an amylin analogue) alone and in combination with semaglutide 2.4 mg (referred to as "Cagrisema") compared to placebo or active comparators (semaglutide or liraglutide) in adults with obesity. Researchers searched electronic databases and identified 3 eligible randomized controlled trials encompassing 430 participants. The pooled analysis found that Cagrisema was associated with significantly greater percentage and absolute body weight reduction compared to semaglutide 2.4 mg alone over 20–32 weeks, though with notably high statistical heterogeneity (I² up to 98%). Cagrilintide monotherapy showed statistically similar weight loss to semaglutide or liraglutide over 26–32 weeks. Regarding safety, treatment-emergent and serious adverse events were broadly comparable across groups; however, gastrointestinal adverse events and vomiting were significantly more frequent with Cagrisema versus semaglutide, while vomiting was significantly lower with cagrilintide monotherapy versus semaglutide or liraglutide. Key limitations include the very small number of included trials (n=3), limited total sample size, short-to-medium follow-up durations, and very high heterogeneity, which tempers confidence in the pooled estimates.
Indian journal of endocrinology and metabolism · Sep 2024DOI ↗ Review
This review paper examines the history, development, and scientific utility of key synthetic tool compounds used to study the melanocortin receptor (MCR) family — a group of five Class A G protein-coupled receptors (GPCRs) involved in diverse physiological processes including pigmentation, steroidogenesis, and energy homeostasis. The authors trace how synthetic derivatives of the endogenous agonist α-MSH, including NDP-MSH (melanotan I), melanotan II (MTII), and SHU9119, have become essential pharmacological tools for the field. The review discusses how these compounds are used to validate cell lines stably expressing melanocortin receptors, serve as reference ligands in high-throughput screening, inform structure-activity relationship (SAR) studies, and act as core ligands in cryo-EM structural investigations of active and inactive receptor complexes. The paper also notes that these tool compounds have served as scaffolds for FDA-approved drugs. Limitations of the review include its descriptive, non-experimental nature and its focus on synthesizing existing literature rather than presenting new empirical data. It provides important context for researchers working on MCR pharmacology but does not itself generate clinical or mechanistic evidence.
ACS pharmacology & translational science · Aug 2024DOI ↗ Animal only
This review paper examines the published preclinical evidence on stable gastric pentadecapeptide BPC 157 as a potential therapeutic agent for intestinal anastomoses and related gastrointestinal conditions in rat models. The authors summarize findings across a range of anastomosis types — including esophagogastric, colocolonic, jejunoileal, and ileoileal — and report that BPC 157 therapy was associated with improved healing outcomes in these animal studies. The review also covers concomitant gastrointestinal disturbances such as esophagitis, sphincter dysfunction, colitis, short bowel syndrome, and major vessel occlusion, as well as dysfunction of the nitric oxide and prostaglandin systems. Additionally, the authors discuss fistula healing (e.g., colocutaneous, gastrocutaneous, vesicovaginal, rectovaginal) as a related phenomenon, framing fistulas as abnormal anastomoses between tissues. The review concludes that both anastomoses and fistulas showed healing responses attributed to BPC 157 in rat models. Limitations include the exclusive reliance on animal data, absence of human clinical trials, and the inherent interpretive limitations of a narrative review format. No controlled human evidence is presented or discussed.
Pharmaceuticals (Basel, Switzerland) · Aug 2024DOI ↗ 🧪 TrialInsufficient
Registered Phase 2 interventional trial (recruiting). People with HIV experience earlier impairments in physical function compared to people in the general population. They also exhibit an earlier presentation and more rapid development of frailty, a multisystemic syndrome of aging characterized by reduced activity, fatigue, slowness, weakness, and weight loss. While exercise can improve physical function in people with HIV, it is less effective in doing so than in the general population and is difficult to sustain in the long-term. The goal of this clinical trial is to learn whether the medic
ClinicalTrials.gov · Aug 2024View trial ↗ Limited · human
This case report describes a 40-year-old male who developed bilateral gynecomastia and biochemical hypogonadotropic hypogonadism after approximately six months of using commercially available performance-enhancing supplements. Laboratory analysis of the three supplements identified several banned performance-enhancing drugs (PEDs): RAD-140 (a selective androgen receptor modulator), MK-677 (a growth hormone secretagogue), and cardarine. In vitro testing also revealed undisclosed hormones — testosterone, estradiol, and growth hormone — present in all three products. Liquid chromatography-mass spectrometry further identified an uncharacterized compound eluting near the testosterone peak. Upon cessation of all supplements, the patient experienced full clinical and biochemical resolution of his symptoms, including normalization of gonadotropin and testosterone levels. The authors argue this case underscores the importance of clinicians considering commercially available supplements as potential covert sources of exogenous PEDs and steroid hormones. Key limitations include the single-patient design, which precludes generalization, the inability to isolate which specific compound(s) caused the adverse effects, and the lack of confirmed identity of the uncharacterized coeluting compound.
JCEM case reports · Aug 2024DOI ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (active not recruiting). This study will look at how much CagriSema lowers blood sugar and body weight in people with type 2 diabetes. CagriSema is a new investigational medicine. Doctors cannot yet prescribe CagriSema. CagriSema will be compared to a medicine called tirzepatide. Doctors can prescribe tirzepatide in some countries. Participants will either receive CagriSema or tirzepatide. Which treatment the participant will receive is decided by chance. For each participant, the study will last for up to 1 year and 4 months.
ClinicalTrials.gov · Aug 2024View trial ↗ Animal only
This preclinical study examined whether two ghrelin mimetics (growth hormone secretagogue receptor 1a agonists), anamorelin and ipamorelin, could reduce cisplatin-induced weight loss, appetite suppression, and vomiting in ferrets — an established animal model of chemotherapy-induced nausea and emesis. In isolated ferret ileum tissue, both compounds inhibited electrically-stimulated gut contractions, with anamorelin showing a greater maximum inhibitory effect. When administered intraperitoneally before and after cisplatin, neither compound reduced acute or delayed vomiting episodes, but both reduced associated weight loss by approximately 24% during the late delayed phase (48–72 hours). Strikingly, when anamorelin was delivered directly into the brain (intracerebroventricularly), it reduced acute emesis by approximately 60%, improved food and water intake during the acute phase by roughly 20–40%, and reduced delayed-phase weight loss by approximately 23%. These findings suggest that anamorelin's anti-emetic effects depend on central nervous system penetration rather than peripheral action. Limitations include the use of a single non-human animal species, small group sizes typical of ferret studies, and the invasive intracerebroventricular route, which is not clinically practical. No human data were generated.
Physiology & behavior · Jul 2024DOI ↗ Animal only
This study investigated the effects of ipamorelin acetate (IPA), a synthetic ghrelin agonist, on the reproductive axis of male Mozambique tilapia (Oreochromis mossambicus), a cichlid fish. Fish received either 5 µg or 30 µg of IPA over 21 days and were compared to untreated controls. The study found that IPA administration produced a dose-dependent increase in food intake. Histological analysis revealed significant increases in primary spermatocytes, secondary spermatocytes, and early spermatids in both treatment groups, while the higher dose also increased late spermatids, lobule area, and lumen area. Serum concentrations of luteinizing hormone (LH) and the fish androgen 11-ketotestosterone (11-KT) were significantly elevated in both IPA groups. Androgen receptor protein expression was significantly upregulated in the high-dose group. No significant differences in hypothalamic or pituitary GnRH-immunoreactive fiber density were observed across groups. The authors conclude that ghrelin signaling may promote meiosis-I stage germ cell development through LH stimulation at the pituitary level and 11-KT and androgen receptor activity at the testicular level. Limitations include the use of a single non-mammalian species, a short treatment duration, and the absence of mechanistic pathway confirmation.
Animal reproduction science · Jul 2024DOI ↗ Limited · human
This sub-analysis leveraged a randomized, double-blind, placebo-controlled trial of 61 people with HIV (PWH) and metabolic dysfunction-associated steatotic liver disease to assess whether tesamorelin remains effective and safe among those specifically on integrase inhibitor (INSTI)-based antiretroviral regimens. Of 38 participants on INSTIs at baseline, 15 (tesamorelin) and 16 (placebo) completed 12 months of follow-up. The study used MRI, proton MR spectroscopy, and DEXA to quantify visceral fat area, hepatic fat fraction, and trunk-to-appendicular fat ratio. The tesamorelin group showed statistically significant reductions in all three body composition endpoints compared to placebo. Metabolic safety outcomes, including rates of hyperglycemia, were similar between arms, and the drug was generally well tolerated. The authors note this is the first dataset specifically addressing tesamorelin use in PWH on INSTI-based regimens—an important gap given that phase III approval trials predated widespread INSTI use. Key limitations include the small sub-group sample size, the sub-analysis design (not powered for this specific comparison), and the predominantly research-selected population, which may limit generalizability.
AIDS (London, England) · Jun 2024DOI ↗ Preclinical
This study investigated whether the copper-bound tripeptide GHK-Cu (glycyl-l-histidyl-l-lysine-Cu²⁺) could reduce lung inflammation and fibrosis in silicosis — a serious occupational lung disease caused by chronic inhalation of crystalline silica (CS) with no approved specific treatment. Researchers first established a silicosis mouse model by exposing mice to CS, then assessed GHK-Cu's effects on lung inflammation and fibrosis. In parallel, they used the RAW264.7 macrophage cell line (an in vitro model of alveolar macrophages) to study cellular mechanisms. Using molecular docking and binding studies, they identified peroxiredoxin 6 (PRDX6) as a potential molecular target of GHK-Cu. The study reported that GHK-Cu bound to PRDX6 and attenuated CS-induced oxidative stress in alveolar macrophages, which was associated with reduced pulmonary inflammation and fibrosis in the mouse model. No significant systemic toxicity was observed in the treated animals. Key limitations include reliance on animal and cell-line models with no human clinical data, and the mechanistic link to PRDX6 requires further validation. The authors conclude that GHK-Cu warrants investigation as a potential therapeutic candidate for silicosis.
Redox biology · Jun 2024DOI ↗ Review
This review article explores phenotypic drug discovery (PDD) as a research framework and uses thymosin alpha-1 (Tα1), a thymic peptide hormone, as a central case study. PDD is described as an approach that screens compounds based on observable effects in cells, tissues, or whole organisms, without requiring prior knowledge of a specific molecular target. The authors contrast PDD with target-based drug discovery and argue that because disease definitions are largely symptom-based, therapeutic development can benefit from a phenotypic lens. The paper discusses how Tα1 has been evaluated in both preclinical and clinical settings, highlighting its complex immunomodulatory properties and its involvement in host-microbe metabolic interactions across multiple targets and metabolites. The authors also address challenges inherent to PDD, including hit validation and target deconvolution, and suggest that advances in big data analytics may help overcome these hurdles. The article further argues that Tα1's broad therapeutic utility can be meaningfully situated within the PDD framework and the modern precision medicine era. As a narrative review, it does not present original experimental data, and its conclusions are shaped by the selection and interpretation of existing literature.
Frontiers in medicine · Jun 2024DOI ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (recruiting). The goal of the study is to assess how tirzepatide impacts bodyweight and cardiovascular risk factors when used in conjunction with healthy nutrition and physical activity in adolescents with obesity and multiple weight related comorbidities. The study will last approximately 76 weeks and may include up to 23 visits. Participants who have completed the primary 72-week GPIX study and have been off treatment for no more than 12 weeks (including the 4-week safety follow-up period), will have the opportunity to receive an additional 156 weeks o
ClinicalTrials.gov · Jun 2024View trial ↗ Animal only
This mouse study investigated therapeutic strategies for hyperphagia, hyperglycemia, and obesity caused by a loss-of-function mutation in the Htr2c gene (Htr2cF327L/Y), which encodes the serotonin 2C receptor (5-HT2CR). Researchers tested three main approaches in male mice fed a high-fat diet. First, they used viral re-expression of functional 5-HT2CR specifically in hypothalamic POMC neurons, finding this was sufficient to reduce food intake and body weight, and restored neuronal responsiveness to lorcaserin (a selective 5-HT2CR agonist). Second, they administered melanotan II, an MC4R agonist, which effectively suppressed feeding and weight gain. Third, they promoted voluntary wheel-running exercise, which reduced high-fat diet consumption and improved glucose homeostasis. The study highlights the importance of the 5-HT2CR–melanocortin pathway in energy balance regulation and suggests MC4R agonists and physical activity may be relevant strategies for individuals carrying rare Htr2c variants. Key limitations include exclusive use of a single male mouse model, a specific engineered mutation, and the gap between rodent models and human metabolic disease.
Endocrinology · May 2024DOI ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (active not recruiting). The main purpose of this study is to determine if retatrutide can significantly lower the incidence of serious heart-related complications or prevent the worsening of kidney function. The trial will enroll adults with body mass index 27 kg/m\^2 or higher and Atherosclerotic Cardiovascular Disease and/or chronic kidney disease. The study will last for about 5 years. Participants will have up to 27 clinic visits with the study doctor.
ClinicalTrials.gov · Apr 2024View trial ↗