Insufficient
SYNCHRONIZE-JP is an ongoing 76-week, randomized, double-blind, parallel-group, multicenter Phase 3 clinical trial evaluating survodutide — a novel dual glucagon receptor/GLP-1 receptor agonist — for obesity disease management in Japanese adults. The study enrolled 274 participants aged ≥18 years with obesity and at least one qualifying complication (type 2 diabetes capped at 30%, hypertension, or dyslipidemia). Participants were randomized 1:1:1 to one of two doses of once-weekly survodutide or placebo, alongside a reduced-calorie diet and increased physical activity. At baseline, the mean age was 53.1 years, mean BMI was 33.2 kg/m², 47.8% were female, and 24.1% had type 2 diabetes; the most common comorbidities were dyslipidemia (81.4%) and hypertension (72.6%). The co-primary endpoints are percentage change in body weight and proportion achieving ≥5% body weight reduction from baseline to Week 76. A subset will also be assessed for liver fat content and body composition. This publication reports only the trial rationale, design, and baseline characteristics; no efficacy or safety outcome data are yet available, which is a key limitation.
Diabetes, obesity & metabolism · May 2026DOI ↗ In vitro
This study investigated whether the gastric pentadecapeptide BPC-157 and two newly designed hybrid analogs (CIARA-1 and CIARA-2) could inhibit acetylcholinesterase (AChE), an enzyme targeted in the treatment of neurodegenerative conditions such as Alzheimer's disease. The hybrid peptides were rationally designed by combining a BPC-157-derived fragment with an arginine-rich C-terminal sequence intended to enhance binding at both the catalytic and peripheral sites of AChE. Inhibitory activity was measured in vitro using a modified Ellman colorimetric assay, with kinetic parameters derived from Lineweaver-Burk plots. All three compounds showed competitive inhibition—meaning they raised the Michaelis-Menten constant (Km) without affecting maximum velocity (Vmax)—indicating direct competition with the substrate at the enzyme's active site. CIARA-1 showed the strongest inhibition (Ki = 0.24 mM; IC50 = 2.52 mM), followed by CIARA-2 and then BPC-157 itself. Results were supported by molecular docking predictions. A key limitation is that inhibitory potencies were substantially lower than those of approved AChE inhibitors. No animal or human data were included. The authors suggest these peptides represent a structural scaffold for further optimization rather than immediate therapeutic candidates.
International journal of molecular sciences · May 2026DOI ↗ Review
This review examines the rationale and emerging evidence for combining Thymosin α1 (Tα1) — a naturally occurring, pleiotropic immunomodulatory peptide — with immune checkpoint inhibitors (ICIs) in the treatment of solid tumors. The authors first outline the biological characteristics of Tα1, highlighting its dual role in enhancing immune competence (e.g., promoting T-cell maturation and activation) while simultaneously regulating excessive immune responses. They then synthesize preclinical and clinical evidence suggesting that Tα1 may address key limitations of ICI monotherapy, including tumor heterogeneity, immunosuppressive tumor microenvironments, and immune-related adverse events (irAEs). The review argues that Tα1 can synergistically remodel the tumor immune microenvironment when combined with ICIs, potentially improving overall response rates. Preliminary clinical findings cited in the review indicate promising efficacy and manageable safety profiles for the combination. The authors acknowledge that the current evidence base relies heavily on early-phase or smaller studies and explicitly call for large-scale, long-term clinical trials to validate sustained benefits. As a narrative review, it does not generate new primary data, and conclusions are limited by the quality and scale of the underlying studies reviewed.
Frontiers in immunology · May 2026DOI ↗ Animal only
This rat study investigated whether BPC 157, a synthetic pentadecapeptide derived from a gastric protein, could protect skeletal muscle tissue from ischemia-reperfusion (I/R) injury. Twenty-four male Wistar rats were divided into four groups (n=6 each): sham surgery, BPC 157 alone, I/R injury alone, and I/R injury treated with BPC 157. I/R was induced by clamping the abdominal aorta for 45 minutes followed by 2 hours of reperfusion; BPC 157 was given intraperitoneally at the end of the ischemia period. The study measured oxidative stress markers (MDA, SOD, TAS, TOS) in serum, gene expression of inflammatory and apoptotic markers (IL-6, HIF-1α, p53, Bcl-2, Bax, Caspase-3) via qRT-PCR, and protein expression (VEGF, eNOS, IL-6, Caspase-3) via immunohistochemistry, alongside histopathological scoring. The authors report that I/R increased oxidative stress, inflammation, and apoptotic signaling, while BPC 157 treatment was associated with reduced oxidative markers, decreased inflammatory and pro-apoptotic gene expression, increased anti-apoptotic Bcl-2, partial restoration of VEGF, and improved muscle histology. Limitations include very small group sizes (n=6), use of a single dose, a single species, and no human data, restricting the generalizability of findings.
Scientific reports · May 2026DOI ↗ Review
This review examines what happens to body weight after patients stop taking glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and newer dual/triple co-agonists used for obesity treatment. The authors note that these medications can produce mean weight losses of 10–30%, far exceeding what is typically achievable through lifestyle changes alone. However, the review highlights that real-world data suggest up to 65% of patients discontinue GLP-1 RAs within one year of starting treatment, and randomized controlled trial data indicate that approximately two-thirds of lost weight is regained within a year of stopping the medication. The review explores the physiological, behavioral, and environmental mechanisms that drive this weight regain once pharmacological appetite suppression is removed. The authors conclude that sustaining weight loss after discontinuation will require integrated, patient-centered approaches that combine ongoing lifestyle interventions, behavioral support, and system-level strategies. As a review article, it synthesizes existing evidence but does not generate new primary data, and its conclusions are limited by the quality and scope of the studies it draws upon.
EClinicalMedicine · May 2026DOI ↗ Insufficient
This News and Perspectives article, authored by JMIR Correspondent Anna Zucker, examines the landscape of GLP-1 receptor agonist prescribing through telehealth platforms for obesity management. The piece highlights a structural concern: while digital health platforms have significantly expanded access to GLP-1 medications, they may not consistently provide adequate clinical follow-up and ongoing support after the initial prescription is issued. The article argues that this "clinical support gap" — encompassing monitoring, behavioral counseling, and longitudinal care — could undermine the potential benefits of these medications and may pose risks to patients. As a News and Perspectives piece, the article does not present original empirical data or a clinical trial; rather, it synthesizes observations and commentary to frame an emerging issue in digital health delivery. Its limitations include the absence of primary data, quantitative analysis, or a systematic review methodology. The piece is best interpreted as expert opinion and advocacy for improved care structures within telehealth-based GLP-1 treatment models, rather than as direct clinical evidence.
Journal of medical Internet research · May 2026DOI ↗ Limited · human
This observational pharmacovigilance study analyzed Individual Case Safety Reports (ICSRs) from the European EudraVigilance (EV) database to investigate whether GLP-1 receptor agonists (semaglutide, liraglutide, exenatide, lixisenatide, dulaglutide) and the dual GLP-1/GIP agonist tirzepatide are disproportionately associated with thyroid cancer-related adverse events. The study retrieved 34,956 ICSRs reported between January 2022 and September 2024. Most adverse events affected adult and elderly female patients, with gastrointestinal disorders being the most commonly reported category. Using disproportionality analysis (Reporting Odds Ratio, ROR), the study found that semaglutide had a statistically significantly lower probability of thyroid cancer-related adverse event reporting compared to tirzepatide (ROR = 0.54, 95% CI 0.37–0.81). The authors acknowledge key limitations inherent to pharmacovigilance databases, including reporting bias, confounding by indication, and the inability to establish causality. They conclude that findings must be interpreted cautiously and that further prospective studies are needed to clarify whether a true causal relationship exists between GLP-1 RAs and thyroid cancer risk.
Pharmacological reports : PR · May 2026DOI ↗ Limited · human
This pharmacovigilance study analyzed reports submitted to the FDA Adverse Event Reporting System (FAERS) to compare biliary adverse events (AEs) across five GLP-1 receptor agonists (GLP-1RAs): semaglutide, tirzepatide, liraglutide, exenatide, and dulaglutide. After deduplication, 3,460 reports were included. Using semaglutide as the reference, the authors calculated proportional reporting ratios (PRR), reporting odds ratios (ROR), and Fisher exact tests across five biliary outcomes: cholelithiasis, cholecystitis, biliary colic, bile duct stone, and cholangitis. The study found that compared with semaglutide, exenatide and tirzepatide showed lower relative reporting for bile duct stone, while exenatide and dulaglutide showed lower relative reporting for biliary colic. Dulaglutide showed higher relative reporting for cholangitis. Exenatide, liraglutide, and tirzepatide all showed higher relative reporting for cholecystitis and cholelithiasis. Sensitivity and subgroup analyses were broadly consistent, though rarer outcomes lost statistical significance. Key limitations include the inherent biases of spontaneous reporting databases (underreporting, confounding by indication, and lack of denominator data), which preclude causal inference. The authors concluded that biliary AE reporting patterns differ meaningfully across agents within the GLP-1RA class.
Digestive diseases and sciences · May 2026DOI ↗ Review
This review synthesizes evidence from randomized controlled trials and high-quality meta-analyses on approved and investigational obesity medications, examining their effects beyond weight loss alone. Medications reviewed include phentermine-topiramate, naltrexone-bupropion, GLP-1 receptor agonists (liraglutide, semaglutide), and newer multiagonist agents (tirzepatide, survodutide, mazdutide, retatrutide, cagrilintide-semaglutide, and amycretin). The authors evaluated impacts across a broad range of obesity-related comorbidities, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, heart failure, cardiovascular disease, obstructive sleep apnea, polycystic ovary syndrome, osteoarthritis, muscle mass, depression, quality of life, food cravings, binge-eating disorders, substance use disorders, and neurodegenerative diseases. The review concludes that GLP-1-based and multiagonist therapies demonstrate beneficial effects across these conditions. Notably, the authors report that while many benefits appear to be mediated through weight reduction, accumulating evidence suggests weight loss-independent mechanisms, particularly for GLP-1 receptor agonist-based therapies. Key limitations include its reliance on synthesized rather than primary data and variability in evidence quality across the individual conditions reviewed.
The lancet. Diabetes & endocrinology · May 2026DOI ↗ Limited · humanPreprint
This large pharmacovigilance study analyzed 20.3 million FDA FAERS adverse event reports (2004–2024) to investigate impaired gastric emptying (IGE) as a potential class-wide adverse effect of GLP-1 receptor agonists (GLP-1 RAs). Researchers identified 6,868 IGE reports across nine GLP-1 RA agents and applied the proportional reporting ratio (PRR) method with sensitivity analyses, supplemented by cross-national validation using 29 reports from Brazil's pharmacovigilance database. The study found that all nine agents exceeded established Evans signal detection criteria, with PRRs ranging from 4.4 (exenatide) to 83.9 (injectable semaglutide). Notably, oral and injectable semaglutide showed comparable PRRs, suggesting a systemic rather than route-dependent mechanism. Tirzepatide prescribed for type 2 diabetes showed a substantially higher PRR than the same drug prescribed for obesity, which the authors interpret as a possible effect of diabetic autonomic neuropathy. A pre-litigation signal analysis was also conducted to account for potential notoriety bias. Key limitations include the inherent constraints of spontaneous pharmacovigilance data—including reporting bias, lack of denominator data, and inability to establish causation—as well as the small cross-national validation sample (n=29). The authors conclude that findings support pre-treatment risk stratification discussions for gastroparesis in GLP-1 RA candidates.
Unknown journal · May 2026DOI ↗ Limited · humanPreprint
This large pharmacovigilance study extracted 412,643 adverse event reports for five GLP-1 receptor agonists (semaglutide, tirzepatide, liraglutide, dulaglutide, and exenatide) from the FDA Adverse Event Reporting System (FAERS) spanning 2004–2024, comparing disproportionality signals using proportional reporting ratios (PRR) and reporting odds ratios (ROR). The study identified 154 drug-event signals overall. The most notable finding was a strong gastroparesis signal for semaglutide (PRR 88.9, 95% CI 85.4–92.6), which the authors describe as substantially higher than prior published estimates and as robust across three pre-specified sensitivity analyses using different comparator groups. All five agents showed statistically significant gastroparesis signals. Gastroparesis reports were consistently female-predominant across all agents (female-to-male ratio 2.7–3.6×). Tirzepatide's adverse event profile was notably dominated by device-usability reports rather than clinical events. Case-fatality rates varied across agents (0.6% to 3.7%). Key limitations include inherent FAERS biases (underreporting, stimulated reporting, lack of denominator data, and confounding by indication), which preclude causal inference or incidence estimation. The authors acknowledge the preprint status of this work.
Unknown journal · May 2026DOI ↗ Animal onlyPreprint
This preclinical study investigated whether the endogenous copper-binding peptide GHK-Cu (glycyl-L-histidyl-L-lysine–copper complex) could mitigate age-related cognitive decline in middle-aged to old C57BL/6J mice (20–21 months). Two delivery routes were compared: short-term intraperitoneal (IP) administration over 5 days and longer-term intranasal (IN) administration over 8 weeks. Hippocampal-dependent spatial learning was assessed via an escape latency task; molecular changes were examined through hippocampal immunohistochemistry and bulk RNA sequencing, with differential gene expression analyzed using DESeq2 and gene set enrichment analysis (GSEA). Both delivery routes were associated with improved escape latency performance in treated mice of both sexes compared to controls, suggesting behavioral rescue of age-related learning deficits. However, the two routes produced divergent hippocampal transcriptomic profiles, implying that delivery method and exposure duration engage distinct molecular aging programs. Key limitations include the exclusive use of a mouse model, the absence of human data, variability in statistical power across outcome measures, and preprint status meaning the findings have not yet undergone formal peer review. The study does not establish causality in humans and is hypothesis-generating for future translational research.
Unknown journal · May 2026DOI ↗ Moderate · human
This systematic review and network meta-analysis (NMA) evaluated the comparative efficacy of pharmacological interventions—at specific dosages—for improving liver fibrosis in adults with metabolism-associated steatotic liver disease (MASLD) and fibrosis stages F1–F3. Researchers searched three databases through July 2025, identifying 13 randomized controlled trials encompassing 3,871 patients and 12 distinct drug regimens. Using both direct comparisons and network meta-analysis, the study found that six interventions—resmetirom (two doses), survodutide, and tirzepatide (three doses)—were significantly more effective than placebo at achieving NASH resolution without worsening fibrosis. Surface Under the Cumulative Ranking (SUCRA) analysis ranked survodutide 6 mg/week highest, followed by tirzepatide 15 mg/week; emricasan 10 mg/day ranked lowest. The authors concluded that survodutide, efruxiferimin, resmetirom, and denifanstat showed the most promise for this population, while emricasan was not supported. Limitations include the moderate number of included trials, potential heterogeneity across study populations and outcome definitions, and the indirect nature of many NMA comparisons, which may limit the precision of the relative effect estimates.
Journal of translational medicine · May 2026DOI ↗ Insufficient
This brief report, authored for nurse practitioners (NPs), examines the clinical and regulatory challenges arising from patient-driven "microdosing" of GLP-1 receptor agonists (semaglutide and tirzepatide) in the context of FDA restrictions on compounded versions following resolution of drug shortages. The authors describe how affordability barriers push patients toward subtherapeutic dosing strategies, unregulated "research-grade" peptides purchased online, and unsupervised sources such as medical spas. The paper outlines specific safety concerns associated with these practices, including pen manipulation, medication sharing, compounded vials, and dosing errors, as well as the side effect profiles encountered. It also explores how provider weight bias may inadvertently drive patients toward unregulated alternatives and offers practical stigma-reduction strategies for clinical encounters. The authors discuss the legal risks of compounded "copies" and acknowledge a narrow legitimate role for compounding in patients with documented allergies. As a brief report rather than an empirical study, the paper does not present original data or a systematic review; its conclusions are based on regulatory context, clinical observation, and expert opinion. Its primary value lies in synthesizing emerging practice-relevant issues for NPs navigating a rapidly evolving regulatory environment.
Journal of the American Association of Nurse Practitioners · May 2026DOI ↗ Animal only
This study investigated whether MOTS-c, a mitochondrial-derived peptide with metabolic and exercise-mimicking properties, could attenuate skeletal muscle loss in cancer cachexia. In vitro, differentiated myotubes treated with MOTS-c showed increased PGC-1α mRNA expression (~85%) and enhanced AMPK phosphorylation (~103%), suggesting activation of mitochondrial biogenesis and energy-sensing pathways. In vivo, male mice implanted with Colon-26 (C26) carcinoma cells developed significant systemic wasting (~9% body weight loss). Daily MOTS-c treatment did not prevent total body weight loss or fat mass loss in these tumor-bearing mice, but it did significantly preserve skeletal muscle mass — notably rescuing quadriceps weight (~12% vs. C26 vehicle controls). Mechanistically, MOTS-c appeared to modulate FOXO signaling and reduce atrogene expression (MuRF1 and Atrogin-1), key mediators of muscle protein breakdown, while promoting mitochondrial biogenesis markers. The authors conclude that MOTS-c partially protects against cachexia-associated muscle deterioration. Key limitations include the exclusive use of male mice, an animal-only in vivo model, and the authors' own acknowledgment that human studies are needed to validate these findings.
Frontiers in medicine · May 2026DOI ↗ Review
This narrative review examines the role of lifestyle interventions before, during, and after treatment with second-generation obesity management medications (OMMs), specifically semaglutide and tirzepatide. The authors note that these agents have demonstrated weight losses of approximately 15–20% in recent trials, prompting a reconsideration of how lifestyle programs should be integrated into obesity care. The review identifies several emerging concerns in the literature, including lean mass loss, nutritional deficiencies, gastrointestinal side effects, and significant weight regain following medication discontinuation. The authors argue that lifestyle modification remains the foundation of obesity treatment but that the focus may need to shift from weight reduction toward broader health promotion in the context of highly effective pharmacotherapy. Key lifestyle strategies discussed include protein intake and physical activity to preserve muscle mass, and dietary approaches to manage gastrointestinal side effects. The review also explores pre-treatment lifestyle programs as potential prerequisites for pharmacotherapy while cautioning that such requirements could limit access and reinforce weight stigma. Limitations include the narrative (non-systematic) design, lack of primary data, and the rapidly evolving evidence base. The authors conclude that optimal timing, frequency, and content of lifestyle interventions alongside OMMs remain unclear and warrant further research.
Current atherosclerosis reports · May 2026DOI ↗ Review
This review article argues that GLP-1 receptor agonists (GLP-1 RAs) — such as semaglutide and tirzepatide — should be understood as catalysts for, rather than replacements of, lifestyle intervention in cardiometabolic care. The authors propose the guiding principle "lifestyle first and lifestyle always, but not lifestyle only," acknowledging that GLP-1 RAs have produced meaningful clinical benefits including substantial weight loss, improved glycemic control, and reduced cardiovascular and renal risk. However, the authors contend that pharmacotherapy alone cannot address the full spectrum of cardiometabolic risk drivers, including sarcopenia, physical deconditioning, poor sleep, psychological stress, and social determinants of health. The article highlights that discontinuation of GLP-1 RAs without structured lifestyle support is commonly associated with weight regain. Key lifestyle pillars emphasized include high-quality nutrition, regular physical activity (including resistance training), restorative sleep, stress management, and social connectedness. The authors advocate for integrated, interprofessional care models combining pharmacologic and lifestyle strategies, supported by systemic and policy-level change. As a narrative review, the paper does not present original data, conduct a systematic literature search, or include a meta-analysis, which limits the directness of its evidentiary contribution.
American journal of lifestyle medicine · May 2026DOI ↗ Review
This clinical review synthesizes current evidence on glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a drug class increasingly used to manage type 2 diabetes, obesity, and expanding metabolic and cardiorenal conditions. The authors describe the physiological mechanisms underlying GLP-1 RA action, survey established and emerging clinical indications, and outline practical safety considerations relevant to growing use in younger, healthier, and more diverse patient populations. A central focus is the management of adverse effects—particularly gastrointestinal intolerance—for which the authors propose a structured algorithm to guide early symptom management in clinical practice. The review also addresses communication strategies intended to support shared decision-making, reduce weight-related stigma, and align therapy with individual patient goals and values. As a narrative review without original data collection, the paper does not generate new clinical outcome data and is subject to the selection biases inherent to non-systematic literature reviews. Nonetheless, it offers a clinically oriented framework intended to help practitioners translate evolving GLP-1 RA evidence into individualized, patient-centered care. No external funding was reported.
EClinicalMedicine · May 2026DOI ↗ Moderate · human
This systematic review and meta-analysis synthesized evidence from three placebo-controlled randomized controlled trials (total n = 258) examining semaglutide in adults with schizophrenia spectrum disorders (SSDs). The authors conducted a preregistered search, pooled outcomes using random-effects meta-analysis, and assessed evidence certainty using GRADE criteria. The included trials tested semaglutide over 26–36 weeks. The study found that, compared to placebo, semaglutide was associated with statistically significant reductions in body weight (approximately −11.3 kg), BMI (approximately −3.6 kg/m²), HbA1c (approximately −0.37%), and fasting glucose. On the safety side, semaglutide was associated with meaningfully higher risks of abdominal pain, vomiting, and constipation, consistent with the known gastrointestinal profile of GLP-1 receptor agonists; no elevated risk of serious adverse events was observed. The authors note that the overall evidence base is limited by a small number of trials, modest combined sample size, and relatively short follow-up durations. No trials of tirzepatide in this population were identified. The authors conclude that semaglutide shows promise as an adjunctive metabolic treatment in SSDs but call for larger, longer trials.
BJPsych open · May 2026DOI ↗ Limited · human
This cross-sectional study investigated circulating levels of MOTS-c — a mitochondria-derived peptide involved in metabolic and immune regulation — in patients with Hashimoto's thyroiditis (HT) compared to healthy controls. A total of 180 participants (90 HT patients and 90 age- and sex-matched healthy controls) were enrolled. The study found that circulating MOTS-c levels were significantly lower in HT patients than in controls. Lower MOTS-c levels were independently associated with insulin resistance and markers of autoimmune burden (such as thyroid autoantibodies). The authors propose that impaired mitochondrial signaling, as reflected by reduced MOTS-c, may contribute to the pathophysiology of thyroid autoimmunity and metabolic dysregulation seen in HT. The study's cross-sectional design limits causal inference — it is unclear whether reduced MOTS-c is a cause or consequence of HT. Additional limitations include the single-timepoint measurement, potential confounders not fully addressed, and the absence of longitudinal follow-up. The findings position MOTS-c as a candidate biomarker linking metabolic dysfunction and immune dysregulation in thyroid autoimmunity, though further prospective and mechanistic research is needed to confirm this relationship.
Journal of clinical medicine · May 2026DOI ↗