Moderate · humanPreprint
This Bayesian network meta-analysis systematically evaluated the dose-dependent efficacy and safety of mazdutide — a dual GLP-1 receptor and glucagon receptor agonist — in adults with obesity or overweight, with or without type 2 diabetes. Researchers searched five major databases through January 2026 and included nine randomized controlled trials comprising 2,292 participants. The study found that, compared with placebo, multiple mazdutide doses were associated with statistically significant improvements across a broad range of cardiometabolic outcomes, including body weight, waist circumference, BMI, HbA1c, fasting plasma glucose, blood pressure, LDL cholesterol, and liver enzymes (ALT). Subgroup analyses suggested that weight loss effects were more pronounced in non-diabetic individuals, while glycemic benefits were greater in those with type 2 diabetes. Gastrointestinal adverse events were notably more frequent with mazdutide relative to placebo, though serious adverse events were not significantly elevated. Key limitations include the relatively small number of included trials (n=9) and total participants, the indirect comparisons inherent to network meta-analysis methodology, potential heterogeneity across trial populations, and the preprint status of this work, meaning it has not yet undergone formal peer review.
Unknown journal · Jun 2026DOI ↗ 🧪 TrialInsufficient
Registered N/A interventional trial (recruiting). This is a 17 - week study consisting of a one - week run - in period and a 16 - week intervention. The 16 - week pilot interventions aims to increase hydration in those beginning GLP - 1 RA therapy. Investigators aim to increase hydration to potentially decrease side effect severity, amount of side effects, and drug discontinuation associated with GLP - 1 RA therapy. The investigators are piloting to assess feasibility and preliminary efficacy of the intervention through examining participant retention, participant feedback, researcher and part
ClinicalTrials.gov · Jun 2026View trial ↗ 🧪 TrialInsufficient
Registered Phase 1/Phase 2 interventional trial (not yet recruiting). Duchenne Muscular Dystrophy (DMD) is a rare, genetic disease that leads to muscle weakness, breathing difficulties, heart disease, and early death. Approximately half of individuals with DMD have elevated body mass indices (BMIs) in the overweight or obesity range. High BMI is due to a combination of factors including limited mobility and steroid medications, which are used to treat DMD. There are new medications, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) that promote weight loss in the general population. GLP-1
ClinicalTrials.gov · Jun 2026View trial ↗ In vitro
This study describes the development of a scalable, chemically defined protocol for differentiating human pluripotent stem cells (hPSCs) into hypothalamic neurons enriched for pro-opiomelanocortin (POMC)-expressing cells, which are key regulators of appetite, energy, and glucose balance. The researchers validated neuronal identity using multiple high-resolution techniques — including MERFISH single-cell transcriptomics, RNA-Seq, and ATAC-Seq — and benchmarked results against human hypothalamic tissue. The protocol was tested across multiple hPSC lines and demonstrated consistent induction of ventral diencephalon and hypothalamic markers, and was designed to be compatible with robotic, high-throughput cell culture platforms. Functional assays showed that derived neurons responded to insulin and the GLP-1 receptor agonist Exendin-4, and displayed transcriptional changes under altered glucose conditions. ATAC-Seq analysis identified candidate regulatory genomic regions associated with hypothalamic development and metabolic traits, and BMI-associated gene enrichment was observed in the derived neurons. Limitations include that this is an in vitro cell model and may not fully recapitulate the complexity of the intact human hypothalamus. No human clinical outcomes were assessed. The platform is positioned as a tool for studying the mechanisms underlying metabolic disease and for therapeutic screening.
Stem cell reports · Jun 2026DOI ↗ Limited · human
This clinical trial examined whether short-term meal replacement therapy (MRT) could reduce liver fat and improve metabolic markers in adolescents with severe obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Seventeen participants aged 12–17 years (mean BMI ~40 kg/m²; mean hepatic fat fraction ~15.6%) completed a 4–8 week MRT program targeting a ~500 kcal/day caloric deficit and at least 5% BMI reduction. Liver fat was measured using magnetic resonance spectroscopy (MRS) at baseline and follow-up. The study found a mean 5.6% absolute reduction in BMI and a statistically significant decrease in hepatic fat fraction, along with improvements in insulin sensitivity, glucose area under the curve, and leptin levels. No significant change in alanine aminotransferase (ALT) was observed. Key limitations include the very small sample size (n=17), absence of a control group, and the short intervention duration, all of which substantially restrict generalizability. The authors conclude that MRT was associated with reductions in liver fat and metabolic improvements in this population and call for larger, controlled trials to assess MRT as part of a broader multimodal treatment strategy for adolescent MASLD.
Childhood obesity (Print) · Jun 2026DOI ↗ Animal only
This preclinical study designed and tested a novel unimolecular dual agonist that combines glucagon-like peptide-1 (GLP-1) and fibroblast growth factor-21 (FGF21) into a single molecule, connected by a thermally responsive elastin-like polypeptide linker intended to form a sustained-release subcutaneous depot. Receptor activity was first confirmed in cell-based assays. The molecule was then tested in male C57Bl/6J mice fed a diet designed to induce advanced metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. The study found that treated mice showed improvements in body weight, liver mass, blood glucose, and cholesterol compared to controls. Histological and molecular analyses indicated reductions in liver fat accumulation, inflammation, and fibrosis, along with decreased expression of inflammatory and fibrotic marker genes and increased hepatocyte proliferation. Limitations include the exclusive use of a single male mouse strain, the absence of female animals, and the inherent translational gap between diet-induced rodent models and human MASH. No human data were generated. The authors conclude that this dual-agonist approach warrants further development as a potential chronic liver disease therapy.
Communications medicine · Jun 2026DOI ↗ Limited · human
This observational matched case-control study used high-field (7 T) ¹H/³¹P magnetic resonance spectroscopy (MRS) to examine skeletal muscle metabolism in newly diagnosed, treatment-naïve people with multiple sclerosis (PwMS) compared to matched healthy controls. Gastrocnemius muscle was assessed both at rest (static MRS) and during post-exercise recovery (dynamic ³¹P-MRS), alongside systemic metabolic profiling via an oral glucose tolerance test (OGTT) measuring glucose, insulin, and GLP-1. The study found that PwMS showed lower resting carnosine levels, elevated pre-exercise inorganic phosphate (Pi), a trend toward a reduced phosphocreatine-to-Pi ratio, and significantly prolonged post-exercise phosphocreatine (PCr) recovery — all indicators of mitochondrial energetic impairment. PwMS also demonstrated a blunted GLP-1 response during OGTT despite preserved insulin sensitivity. Notably, higher PCr levels correlated with greater GLP-1 response only in PwMS, suggesting a muscle-systemic metabolic link specific to the disease. The authors conclude that skeletal muscle mitochondrial dysfunction is detectable at MS onset, even before significant systemic metabolic disruption occurs. Limitations include relatively small sample size, a single muscle group assessed, and the cross-sectional design precluding causal inference.
Scientific reports · Jun 2026DOI ↗ Review
This narrative review examines the potential ocular effects of geroprotective agents — pharmacologic compounds studied for longevity and systemic aging benefits — with a focus on their relevance to age-related eye diseases including age-related macular degeneration (AMD), diabetic retinopathy (DR), retinal vein occlusion (RVO), and glaucoma. The authors argue that shared mechanisms of neurodegeneration, microvascular injury, and chronic inflammation underlie both systemic aging and major retinal diseases, making geroprotectors a pharmacologically relevant class for ophthalmic consideration. The review covers a broad range of agents: GLP-1 receptor agonists, metformin, SGLT-2 inhibitors, statins, cannabinoids, calcium channel blockers, spermidine, taurine, NAD+ precursors, rapamycin, and mifepristone. The authors note that GLP-1 receptor agonists have been associated with potential glaucoma risk reduction but also with unconfirmed reports of nonarteritic anterior ischemic optic neuropathy. The review acknowledges that ocular effects of these agents are incompletely characterized, variably reported, and sometimes controversial. Key limitations include reliance on heterogeneous observational and preclinical data, absence of dedicated ophthalmic clinical trials, and potential confounding in real-world studies. The authors aim to support clinical awareness and identify gaps for future investigation.
Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics · Jun 2026DOI ↗ Review
This narrative review proposes a novel conceptual framework for integrating GLP-1 receptor agonists (GLP-1 RAs) into bariatric surgical care, drawing an analogy from oncology's neoadjuvant and adjuvant treatment models. The authors suggest that GLP-1 RAs used before surgery ("neoadjuvant") could reduce perioperative risk—particularly in super-obese patients—by promoting early weight loss and improving dyslipidemia. Used after surgery ("adjuvant"), GLP-1 RAs may address weight regain and sustain metabolic improvements in patients with suboptimal surgical outcomes. The review synthesizes findings from prospective trials, retrospective analyses, and meta-analyses, noting that preoperative GLP-1 RA use appears generally safe but requires monitoring for metabolic adaptation and a potential "ceiling effect" on postoperative results. The authors introduce a proposed "perioperative management ladder" as a structured decision-making tool. Importantly, the framework is described as primarily hypothesis-generating and intended to inform the design of future randomized controlled trials. Key limitations include the review's narrative (non-systematic) methodology, reliance on heterogeneous primary studies, and the absence of original data.
Current obesity reports · Jun 2026DOI ↗ Limited · human
This systematic review and meta-analysis examined whether glucagon-like peptide-1 receptor agonists (GLP-1RAs) — medications commonly used for type 2 diabetes and obesity — are associated with an increased risk of diabetic macular edema (DME). Researchers searched five major databases through October 2025 and ultimately included 13 retrospective cohort studies (published 2021–2025) drawn from large real-world databases, all involving patients with diabetes who did not have DME at baseline. Using random-effects models, the study found that the pooled incidence proportion of new-onset DME among GLP-1RA users was approximately 14%. Compared with mixed antihyperglycemic therapies, GLP-1RA use was not significantly associated with increased DME risk (HR: 0.81, 95% CI: 0.52–1.26). GLP-1RAs were associated with a higher relative risk of DME compared to SGLT-2 inhibitors (HR: 1.50, 95% CI: 1.17–1.94), but not compared to DPP-4 inhibitors. The authors rated the overall certainty of evidence as very low, citing high statistical heterogeneity (I² = 99.8%), reliance on retrospective observational designs with inherent confounding risks, and variability across database sources. The study concluded that current evidence does not support a clear overall increased DME risk with GLP-1RA use but called for prospective studies to better characterize comparative retinal safety.
Canadian journal of ophthalmology. Journal canadien d'ophtalmologie · Jun 2026DOI ↗ Limited · human
This retrospective cohort study examined whether a documented GLP-1 receptor agonist prescription history (within one year before surgery) was associated with differences in one-year patient-reported outcomes (PROMs), patient satisfaction, and complication rates following primary total hip arthroplasty (THA). Researchers analyzed 12,749 patients who underwent THA at a single tertiary medical center between 2016 and 2022, of whom 145 had a prior GLP-1 prescription. Multivariable logistic regression was used to adjust for confounders. The study found no statistically significant difference between GLP-1 users and non-users in achieving clinically meaningful improvements in hip pain and function (PASS and MCID thresholds) or patient satisfaction at one year. However, GLP-1 prescription history was associated with reduced odds of 90-day hospital readmission (OR 0.47) and a higher rate of 90-day medical complications (9.66% vs. 6.01%). No significant differences were observed in length of stay, 90-day emergency visits, or two-year implant complication rates. The authors caution that the small exposed cohort (n=145) limits statistical power, and the retrospective, single-center, observational design precludes causal inference. Confounding by indication (e.g., GLP-1 users having more metabolic comorbidities) may also influence results.
Hip international : the journal of clinical and experimental research on hip pathology and therapy · Jun 2026DOI ↗ Animal onlyPreprint
This mouse study investigated the effects of semaglutide, a GLP-1 receptor agonist (GLP-1 RA), administered from preconception through lactation in dams fed either a high-fat diet (HFD) or a standard diet. Researchers assessed metabolic outcomes in both the treated mothers and their offspring, who were weaned onto a standard diet. The study found that semaglutide improved body composition and glucose metabolism in HFD-fed dams during pregnancy, and these benefits persisted approximately 10 weeks after weaning even after treatment was discontinued. Offspring born to HFD-fed, untreated dams showed impaired glucose homeostasis and hepatic steatosis (fatty liver) at 18 weeks of age. These metabolic disturbances were attenuated in offspring whose mothers received semaglutide. Notably, semaglutide treatment did not adversely affect conception rates or fetal viability. The authors conclude that GLP-1 RA therapy during the perinatal period may improve both maternal and offspring metabolic health in an obesity mouse model, and they call for further investigation into GLP-1–based therapies in this context. Key limitations include the exclusive use of a mouse model, limiting direct translation to human pregnancy, and the fact that this appears to be a preprint not yet formally peer-reviewed.
Unknown journal · Jun 2026DOI ↗ Limited · human
This retrospective federated cohort study used the TriNetX US Collaborative Network to examine whether GLP-1-based therapy (semaglutide or tirzepatide) was associated with lower rates of ICD-10-documented heart failure (HF) or respiratory failure (RF) in non-diabetic adults with rheumatoid arthritis (RA) and obesity (BMI ≥30 kg/m²). Patients were required to have baseline disease-modifying antirheumatic drug (DMARD) use, and those with diabetes or overlapping systemic autoimmune diseases were excluded. After propensity score matching on 68 covariates (1:1), 3,483 patients remained per cohort. The study found that GLP-1-based therapy was associated with a substantially lower hazard of first post-landmark composite HF or RF events during days 91–365. In absolute terms, the primary composite occurred in 0.7% of GLP-1 users versus 1.8% of never-users, corresponding to roughly one fewer event per 100 patients. Heart failure and respiratory failure analyzed separately showed directionally consistent lower hazards, though individual event counts were small. The authors acknowledge that the findings are hypothesis-generating only, are limited by the retrospective, administrative-data design and potential residual confounding, and require prospective validation before informing clinical practice.
Clinical rheumatology · Jun 2026DOI ↗ 🧪 TrialInsufficient
Registered observational trial (enrolling by invitation). The goal of this observational study is to identify the impact of incretin-based obesity medications (e.g., GLP-1 and GLP-1/GIP) on health and economic outcomes among adults who get their health insurance through their employers. The main questions it aims to answer are: 1. Is obesity medication usage is associated with reduced body mass index (BMI) and weight? 2. Is obesity medication usage is associated with reduced utilization of emergency department and inpatient care or obesity-related conditions over time? 3. Is obesity medication
ClinicalTrials.gov · Jun 2026View trial ↗ Limited · human
This prospective, matched controlled study used continuous glucose monitoring (CGM) via FreeStyle Libre to characterize glycaemic patterns during Ramadan 2025 in 54 adults with insulin-treated diabetes. Three matched groups of 18 participants each were compared: type 2 diabetes on basal-bolus insulin alone (BB), type 2 diabetes on basal-bolus insulin plus adjunctive semaglutide or tirzepatide (BB+), and type 1 diabetes on basal-bolus insulin. CGM data were collected over 28 days pre-Ramadan and 29 days during Ramadan. The study found that dysglycaemia was predominantly driven by the post-iftar (meal-breaking) period. The BB group showed marked deterioration in glycaemic control during non-fasting hours. In contrast, the BB+ group demonstrated significantly better time-in-range (74.4% vs. 36.8%), a lower glucose management indicator (6.9% vs. 8.3%), and an approximately 61% reduction in post-iftar glucose excursions, without increased hypoglycaemia or treatment discontinuations. Limitations include a relatively small matched sample size, a single Ramadan observational period, and non-randomized group assignment, which may introduce residual confounding despite matching.
Diabetes research and clinical practice · Jun 2026DOI ↗ Review
This systematic review examined existing evidence on the use of second-generation incretin analogs — specifically semaglutide (a GLP-1 receptor agonist) and tirzepatide (a dual GLP-1/GIP receptor agonist) — in adults with type 1 diabetes (T1D) or latent autoimmune diabetes in adults (LADA). Researchers screened 3,053 records from six major databases and ClinicalTrials.gov, ultimately identifying 11 eligible publications. These comprised two systematic reviews, one post hoc subgroup analysis, six narrative or consensus reviews, and two LADA case reports. Three key themes emerged from the synthesis: (1) LADA is frequently misdiagnosed or diagnosis is delayed due to its heterogeneous presentation; (2) both tirzepatide and semaglutide show potential benefits in LADA and in certain T1D subtypes, particularly in individuals retaining residual beta-cell function; and (3) existing clinical management frameworks may guide practice while robust trial data are awaited. The authors concluded that current evidence is promising but moderate in quality, and that well-designed, adequately powered randomized controlled trials in clearly defined LADA and T1D populations are needed to establish long-term efficacy and safety. Notable limitations include the small number of eligible studies, the predominance of review-level and narrative publications, and only two primary patient-level reports.
Journal of the American Association of Nurse Practitioners · Jun 2026DOI ↗ 🧪 TrialInsufficient
Registered N/A interventional trial (recruiting). Obese patients exhibit considerable heterogeneity and complex comorbidities, making long-term effective management challenging with monotherapy. While bariatric surgery remains the most effective weight-loss intervention, postoperative weight regain and metabolic deterioration remain significant concerns. glucagon-like peptide-1 receptor agonists (GLP-1RA) offer distinct advantages for weight loss and metabolic control, and their combination with surgery may produce synergistic effects. This study investigates the efficacy and safety of bariatr
ClinicalTrials.gov · Jun 2026View trial ↗ Strong · human
The GLORY-2 trial was a double-blind, placebo-controlled, phase 3 randomized clinical trial evaluating the efficacy and safety of mazdutide — a once-weekly subcutaneous glucagon and GLP-1 receptor dual agonist — for weight reduction in Chinese adults with obesity (BMI ≥30). Conducted across 27 hospitals in China from December 2023 to November 2025, the trial enrolled 461 participants (64% female; mean age ~34 years; mean BMI ~34.3), including 16.1% with type 2 diabetes. Participants were randomized 2:1 to receive 9 mg mazdutide or placebo weekly for 60 weeks alongside lifestyle interventions. The co-primary outcomes were percentage change in body weight and proportion achieving ≥5% weight loss at week 60. The mazdutide group achieved a mean body weight reduction of approximately 16.65% from baseline, compared with 1.50% in the placebo group — a statistically significant between-group difference of approximately 15.15%. Gastrointestinal adverse reactions were more common in the mazdutide group than in the placebo group. Key limitations include the single-ethnicity (Chinese) population, limiting generalizability, and a relatively young mean participant age. The trial was industry-relevant and registered on ClinicalTrials.gov (NCT06164873).
Strong · human
The SYNCHRONIZE-1 trial was a phase 3, double-blind, randomized controlled trial evaluating survodutide — an investigational dual glucagon receptor and GLP-1 receptor agonist — for weight management in adults with obesity (BMI ≥30, or ≥27 with an obesity-related complication) who did not have diabetes. A total of 725 participants were randomized 1:1:1 to one of two dose levels of once-weekly subcutaneous survodutide or placebo, alongside lifestyle counseling, over 76 weeks. The study found that both survodutide groups achieved significantly greater mean body weight reductions compared to placebo (-12.2% and -13.0% versus -5.4%). Approximately 72% of participants in each survodutide group achieved at least 5% body weight reduction, compared to about 46% in the placebo group. The primary analysis used a treatment-regimen estimand accounting for early discontinuations and protocol deviations. Limitations include the relatively short 76-week duration for a chronic condition, the exclusion of people with diabetes, and industry funding by Boehringer Ingelheim. Long-term cardiovascular and safety outcomes remain to be established in ongoing or future trials.
The New England journal of medicine · Jun 2026DOI ↗ Moderate · human
The SYNCHRONIZE-MASLD trial investigated survodutide — a dual glucagon receptor/GLP-1 receptor agonist — in 216 adults with obesity and at-risk metabolic dysfunction-associated steatotic liver disease (MASLD). Participants were randomized 2:1 to once-weekly subcutaneous survodutide 6.0 mg (n=146) or placebo (n=70) for 48 weeks. The trial had two co-primary endpoints: ≥30% reduction in MRI-assessed liver fat content (LFC) and percentage change in body weight from baseline to week 48. Both endpoints were met. The study found that 84.2% of survodutide-treated participants achieved ≥30% LFC reduction versus 24.3% on placebo. Mean body weight decreased by 12.2% with survodutide compared to 1.0% with placebo. The most common adverse events were gastrointestinal in nature, typically mild-to-moderate and concentrated during dose escalation. Key limitations include the relatively short 48-week duration, which precludes conclusions about long-term outcomes such as fibrosis regression or cardiovascular events, a modest sample size, and recruitment restricted to the United States and Spain, limiting generalizability. The study was funded by the manufacturer and used surrogate endpoints rather than hard clinical outcomes.
Nature medicine · Jun 2026DOI ↗