🧪 TrialInsufficient
Registered Phase 2 interventional trial (completed). This study is designed to test how well once-weekly MET097 (an ultra-long-acting GLP-1 receptor agonist) works to treat adults with obesity or overweight and type 2 diabetes mellitus (T2DM) compared to placebo. MET097 or placebo will be administered to individuals via subcutaneous injection once weekly for 28 weeks. If an individual is randomly assigned to MET097 they will receive one of four different dose regimens.
ClinicalTrials.gov · Mar 2025View trial ↗ 🧪 TrialInsufficient
Registered Phase 4 interventional trial (recruiting). The main purpose of this study is to assess the effectiveness of adding tirzepatide to ixekizumab therapy in standard clinical practice in participants with active PsA and obesity or overweight with at least 1 weight-related comorbidity. The study will last up to 12 months.
ClinicalTrials.gov · Mar 2025View trial ↗ Review
This review paper provides a broad overview of glucagon-like peptide-1 (GLP-1), an incretin hormone secreted primarily by intestinal L-cells, pancreatic α-cells, and the central nervous system, and its therapeutic relevance in type 2 diabetes mellitus (T2DM). The authors describe how GLP-1 promotes glucose homeostasis by stimulating insulin secretion, slowing gastric emptying, reducing food intake, and supporting β-cell proliferation. The paper surveys existing GLP-1-based pharmacological strategies, including GLP-1 receptor agonists (single, dual, and triple agonists) and dipeptidyl peptidase-4 (DPP-4) inhibitors, noting that both preclinical and clinical evidence supports their role in improving glycemic control. The review then shifts focus to emerging, non-pharmacological-style strategies: enhancing endogenous GLP-1 production through various physiological and molecular stimuli, and promoting intestinal L-cell differentiation as a means to expand the body's own GLP-1-secreting capacity. The authors frame L-cell differentiation as a particularly promising future therapeutic avenue. As a narrative review, the paper synthesizes existing literature rather than generating new primary data, and its conclusions are limited by the scope and quality of the studies it cites.
Diabetology & metabolic syndrome · Feb 2025DOI ↗ Moderate · human
This paper reports a prespecified subgroup analysis from a phase 2 randomized controlled trial examining how sex and baseline BMI influenced the efficacy and safety of survodutide, a dual glucagon/GLP-1 receptor agonist, in adults without diabetes who had a BMI ≥27 kg/m². A total of 387 participants were randomized to one of four once-weekly subcutaneous survodutide doses or placebo over 46 weeks, which included a 20-week dose-escalation phase followed by a 26-week maintenance phase. The study found that, across survodutide-treated groups, females experienced greater reductions in both bodyweight and waist circumference compared with males. Participants who started with a lower baseline BMI showed proportionally greater bodyweight reductions, while those with a higher baseline BMI showed greater absolute reductions in waist circumference. Adverse event rates were broadly comparable across sex and BMI subgroups, with nausea being the most common gastrointestinal side effect reported in all subgroups. Key limitations include the descriptive (non-inferential) nature of the subgroup analyses, the relatively modest sample size when subdivided by subgroup, and potential confounding from COVID-19-related treatment discontinuations. These findings suggest differential responses by sex and baseline BMI, but the subgroup design limits causal conclusions.
Diabetes, obesity & metabolism · Jan 2025DOI ↗ Insufficient
This cross-sectional pilot study examined the direct-to-consumer market for compounded glucagon-like peptide-1 (GLP-1) receptor agonists in Colorado. Researchers conducted Google searches of business websites advertising compounded GLP-1 products for weight loss across census-defined statistical areas between March and April 2024. They identified 93 websites corresponding to 188 physical locations. Most businesses were categorized as medical/health spas or weight loss services. Semaglutide was the most commonly advertised product (92/93 sites), followed by tirzepatide (40/93). Some sites advertised combination formulations including B vitamins, BPC-157 (flagged by the FDA as unsafe for compounding), and other additives. Seven sites advertised oral formulations. Notably, 41 of 93 websites referenced FDA approval in their product descriptions—a potentially misleading claim, as compounded products are not FDA-approved—and 5 sites incorrectly referred to products as "generic." The study's limitations include its focus on a single state, reliance on publicly available website data, and its pilot/cross-sectional design, which limits generalizability. The authors conclude that regulatory action is needed to address misleading advertising and safety concerns in this market.
Journal of pharmaceutical policy and practice · Dec 2024DOI ↗ Moderate · human
This meta-analysis pooled data from 18 treatment arms across multiple randomized controlled trials (total n = 1,029 participants) to evaluate the effect of injectable survodutide — a dual glucagon and GLP-1 receptor agonist — on obesity-related outcomes. Searches were conducted across major databases through August 2024. Using a random-effects model, the authors found that survodutide was associated with statistically significant reductions in body weight (weighted mean difference: −8.33 kg), BMI (−4.03 kg/m²), and waist circumference (−6.33 cm) compared to control groups. Subgroup analyses suggested that longer intervention durations (more than 16 weeks) and higher doses were associated with greater reductions in weight and waist circumference, a pattern also supported by meta-regression. Key limitations include very high statistical heterogeneity for weight (I² = 99.6%) and waist circumference (I² = 99.5%), which may reflect substantial differences in study populations, doses, and durations across the included trials. The relatively small total participant count and the emerging nature of the evidence base for survodutide also limit the certainty of conclusions. The findings suggest a potential role for survodutide in weight management, but the high heterogeneity warrants cautious interpretation.
Diabetology & metabolic syndrome · Nov 2024DOI ↗ 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 ↗ 🧪 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 ↗ 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 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 ↗ 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 ↗ 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 ↗ 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 ↗ 🧪 TrialInsufficient
Registered Phase 1/Phase 2 interventional trial (active not recruiting). This is a single site, double-blind, placebo-controlled, crossover trial to quantify the effects of combination adjunctive therapy on glycemic control, ketogenesis during insulinopenia, insulin resistance, and diabetes burden and quality of life.
ClinicalTrials.gov · Jan 2023View trial ↗ Animal only
This preclinical study investigated the neurological mechanisms by which obesity medications suppress food intake, focusing on proglucagon (PPG)-expressing neurons in the nucleus of the solitary tract (PPG-NTS). Using single-nucleus RNA sequencing and histochemistry, researchers characterized gene expression profiles of PPG-NTS neurons in rodents, finding that serotonin 2C receptors (5-HT2CR) — the target of lorcaserin — were widely expressed in these neurons, while GLP-1 receptors and melanocortin-4 receptors were not. Lorcaserin was found to significantly activate PPG-NTS neurons. When PPG-NTS neurons were virally ablated, lorcaserin lost its ability to suppress food intake, whereas the MC4R agonist melanotan-II retained its effect, confirming the functional role of 5-HT2CR expression in these neurons. Additionally, combining lorcaserin with GLP-1R agonists liraglutide or exendin-4 produced greater food intake reduction than either drug alone. The study concludes that PPG-NTS neurons are a necessary mechanistic link for lorcaserin's appetite-suppressing effects and suggests that combining 5-HT2CR and GLP-1R agonists may enhance therapeutic outcomes. Key limitations include that all experiments were conducted in animals, and translational relevance to humans remains to be established.
Molecular metabolism · Dec 2022DOI ↗ 🧪 TrialLimited · human
Registered Phase 3 interventional trial (completed), with sponsor-posted results. This study will compare the new medicine IcoSema, which is a combination of insulin icodec and semaglutide, taken once a week, to semaglutide taken once a week in people with type 2 diabetes. The study will look at how well IcoSema controls blood sugar level in people with type 2 diabetes compared to semaglutide. Participants will either get IcoSema or semaglutide. Which treatment participants get is decided by chance. IcoSema is a new medicine that doctors cannot prescribe. Doctors can already prescribe semaglut
ClinicalTrials.gov · Feb 2022View trial ↗ 🧪 TrialInsufficient
Registered observational trial (active not recruiting). Empagliflozin, a sodium glucose co-transporter 2 (SGLT-2) inhibitor, was launched as a treatment for type 2 diabetes mellitus (T2DM) in the U.S. in August 2014. In contrast with several previous cardiovascular outcomes trials, which failed to demonstrate an association with a higher or a lower risk of cardiovascular outcomes associated with members of other recently marketed antidiabetic classes, the EMPA-REG OUTCOME trial has shown that patients at high cardiovascular risk randomized to empagliflozin vs. placebo, were associated with a r
ClinicalTrials.gov · Dec 2017View trial ↗