Animal only
This study investigated whether the mitochondrial-derived peptide MOTS-c could protect the neonatal heart from hyperoxia-induced injury. Using neonatal mice exposed to 85% oxygen as an in vivo model and the rat cardiomyocyte cell line H9C2 as an in vitro model, researchers found that hyperoxia caused cardiac hypertrophy, fibrosis, and dysfunction, alongside reduced circulating MOTS-c levels. Administration of MOTS-c was reported to markedly reduce these pathological changes and restore cardiac function in the mouse model. Mechanistically, the study found that hyperoxia activates a KEAP1–PGAM5–AIFM1 signaling axis, triggering a ROS-specific form of programmed cell death called oxeiptosis. MOTS-c appeared to interact directly with KEAP1, preserving its binding to PGAM5 and thereby preventing nuclear translocation of AIFM1, the downstream executioner of oxeiptosis. Overexpression of KEAP1 abolished MOTS-c's protective effects, supporting KEAP1 as a key target. Limitations include exclusive reliance on animal and cell-line models with no human data, a relatively narrow mechanistic focus, and the absence of long-term outcome measures. These findings are preclinical and require validation in human studies before clinical conclusions can be drawn.
Life sciences · May 2026DOI ↗ Review
This narrative review, aimed at obstetricians and gynecologists, synthesizes current evidence on GLP-1 receptor agonists (e.g., semaglutide) and dual GLP-1/GIP agonists (e.g., tirzepatide) as they relate to women's health. The authors highlight that phase 3 trials have reported 15–21% body weight reduction with these agents, with tirzepatide showing greater efficacy than semaglutide. In women with polycystic ovary syndrome (PCOS), the authors cite meta-analyses finding improvements in insulin resistance, androgen levels, and ovulation rates. Regarding contraception, the review notes that tirzepatide's gastric-emptying delay has prompted manufacturer guidance about backup contraception around initiation and dose escalation. On pregnancy safety, the authors describe emerging human cohort data suggesting no significantly increased risk of major congenital malformations from inadvertent early pregnancy exposure, while noting that animal teratogenicity data still warrant caution. Perioperative guidance has shifted toward individualized risk-stratified approaches rather than blanket discontinuation. The authors call for formal pregnancy registries to address persistent knowledge gaps. As a review, this paper does not generate new primary data, and its conclusions are limited by the underlying evidence base, which in several areas remains preliminary or indirect.
Current opinion in obstetrics & gynecology · May 2026DOI ↗ Review
This narrative review examines whether tirzepatide — a dual GIP/GLP-1 receptor agonist — may act as a disease-modifying therapy in obesity-related obstructive sleep apnea (OSA), beyond its well-established effects on weight reduction. The authors searched PubMed, Scopus, and Web of Science through January 2026, synthesizing evidence from randomized controlled trials, meta-analyses, and mechanistic studies on incretin-based therapies in obesity and OSA. The review reports that tirzepatide is associated with meaningful reductions in apnea-hypopnea index (AHI) alongside significant weight loss. Notably, the authors propose that OSA improvements may not be fully explained by weight loss alone, highlighting potential weight-independent mechanisms such as modulation of systemic inflammation, improvements in insulin sensitivity, changes in adipokine profiles, and effects on autonomic regulation and ventilatory chemosensitivity. The authors acknowledge that current evidence is insufficient to definitively separate weight-dependent from weight-independent effects, and they call for dedicated mechanistic and long-term clinical studies. A key limitation is the review's narrative — rather than systematic — design, which introduces selection bias. The paper frames tirzepatide as a potential shift from purely device-based OSA management toward integrated, pathophysiology-driven treatment strategies, but stops short of confirming disease-modifying status.
Life (Basel, Switzerland) · May 2026DOI ↗ Limited · humanPreprint
This observational cohort analysis describes weight-loss outcomes and adverse event rates in 503 overweight adults who completed six months of the "Trimsulin Weight Loss Program," a nutraceutical regimen combining two proprietary products (a powdered drink mix and a capsule) with a structured diet and exercise protocol. The authors compare their results descriptively — without inferential statistics — to published real-world data for the prescription GLP-1 receptor agonist semaglutide and the dual GIP/GLP-1 agonist tirzepatide. The study reports that Trimsulin participants experienced mean weight reductions of 7.3% at 3 months and 14.1% at 6 months, numerically exceeding the comparator figures drawn from a separate published cohort. Adverse events were self-reported by 4.8% of Trimsulin participants versus much higher rates cited for the pharmacological comparators. Key limitations are substantial: there is no randomization, no placebo or active control arm, no blinding, no direct head-to-head comparison, reliance on self-reported adverse events, a highly selected completer-only analysis (503 of 1,000+ enrollees), differing baseline BMI profiles across cohorts, and the absence of any inferential statistical testing. The program's dietary and behavioral components cannot be disentangled from any supplement effect. The authors acknowledge the need for randomized controlled trials. The paper is identified as a preprint.
Unknown journal · May 2026DOI ↗ Animal only
This study investigated an engineered variant of the mitochondria-derived peptide MOTS-c, called R13A-MOTS-c, designed to overcome the poor cellular permeability of the wild-type peptide. The researchers substituted arginine at position 13 with alanine to increase hydrophobicity, then characterized the modified peptide's uptake mechanism, showing through competition assays and knockdown experiments that it enters cells via the LAT1 amino acid transporter. In vitro, R13A-MOTS-c was reported to reduce inflammatory markers, oxidative damage, and mitochondrial dysfunction in mouse lung epithelial (MLE-12) cells exposed to radiation. In vivo, C57BL/6 mice receiving thoracic irradiation (20 Gy) and treated with intraperitoneal R13A-MOTS-c showed attenuated pulmonary inflammation, oxidative stress, and mitochondrial impairment compared to controls. The proposed mechanism centers on Nrf2 pathway activation, supported by evidence of increased nuclear Nrf2 translocation and upregulation of downstream target genes; protective effects were lost when LAT1 or Nrf2 was inhibited or knocked out. Key limitations include exclusive use of animal and cell models with no human data, a single radiation dose and treatment regimen tested, and the need for further pharmacokinetic and safety characterization before clinical translation.
Redox biology · May 2026DOI ↗ Limited · human
This case series describes two patients with severe obesity who developed moderate-to-severe cutaneous allodynia — a condition where normally non-painful stimuli such as touch or mild temperature change cause pain — while being treated with the dual GLP-1/GIP receptor agonist tirzepatide for weight management. In both cases, the onset of allodynia was temporally linked to dose escalation, occurring at higher doses, and resolved upon discontinuation of the drug. The allodynia varied between static and dynamic types across the two patients. The authors reviewed the tirzepatide U.S. prescribing information and found no prior documentation of skin pain or allodynia as an adverse event, though a prior FDA Adverse Event Reporting System (FAERS) pharmacovigilance analysis had identified rare allodynia signals across six GLP-1RAs. The authors assert this is the first case series specifically reporting allodynia with tirzepatide. Key limitations include the very small sample size (n=2), absence of a control group, and the inherent inability to establish causality from case reports alone. The temporal association and resolution upon drug withdrawal do, however, provide a suggestive signal warranting further investigation.
The American journal of case reports · May 2026DOI ↗ Review
This narrative review evaluates whether incretin-based therapies — specifically GLP-1 receptor agonists (e.g., semaglutide) and dual GLP-1/GIP receptor agonists (e.g., tirzepatide) — warrant consideration as first-line antihypertensive agents. The authors synthesize findings from recent large-scale trials demonstrating that these agents are associated with significant reductions in body weight, blood pressure, and adverse cardiovascular outcomes. Mediation analyses cited in the review suggest that weight loss accounts for a substantial portion of the observed blood pressure reductions; however, the authors also highlight putative direct mechanisms, including improvements in vascular function, renal sodium handling, and neurohumoral pathway modulation. The review notes that beneficial effects on blood pressure appear consistent across diverse patient populations, including those without established hypertension. A key limitation acknowledged by the authors is the absence of randomized controlled trials specifically designed with blood pressure as a primary endpoint. Based on the available evidence, the authors conclude that incretin-based therapies may have an emerging role in hypertension management guidelines, particularly for selected high-risk populations. As a review article, conclusions are dependent on the quality and interpretation of the underlying primary studies cited.
Current hypertension reports · May 2026DOI ↗ Review
The 11th Cardiovascular Outcome Trial (CVOT) Summit (November 2025) was a virtual multidisciplinary conference convening experts in endocrinology, diabetology, cardiology, nephrology, hepatology, and general practice to review recent outcome trials and emerging therapies along the cardiovascular-kidney-metabolic (CKM) disease continuum. The report summarizes key 2025 developments, including the first head-to-head CVOT (SURPASS-CVOT), the CONFIDENCE trial examining combination therapy with finerenone (a non-steroidal mineralocorticoid receptor antagonist) and empagliflozin (an SGLT2 inhibitor), the ATTAIN-1 trial of the oral GLP-1 receptor agonist orforglipron, and the BaxHTN trial of the aldosterone synthase inhibitor baxdrostat. The report also covers updated clinical guidelines, policy developments, advances in continuous glucose and ketone monitoring technology, and emerging pharmacological strategies for metabolic liver disease and type 1 diabetes. As a conference summary report rather than a primary trial, this document does not present original trial data and primarily synthesizes and contextualizes findings from multiple studies. Key limitations include the narrative, consensus-driven format and the absence of new primary data.
Cardiovascular diabetology · May 2026DOI ↗ Limited · human
This study investigated the role of two mitochondrial-derived peptides (MDPs) — humanin (HN) and MOTS-c — in atrial fibrillation (AF), a common heart rhythm disorder. Researchers first examined human atrial tissue using public gene expression data, immunohistochemistry, and immunofluorescence, and measured plasma levels in a matched cohort of 39 AF patients and 39 sinus rhythm controls. They found that both peptides were significantly downregulated in AF tissue, with levels inversely correlated with fibrosis extent. Plasma MOTS-c was also reduced in AF patients and inversely correlated with NT-proBNP, a heart stress biomarker. Using an angiotensin II (AngII)-induced mouse AF model (n=36, male C57BL/6J), the study found that treatment with HNG (an HN analogue) or MOTS-c reduced AF inducibility and attenuated atrial fibrosis and hypertrophy. Peptide treatment was associated with improved mitochondrial structure, reduced fission proteins (Drp1, Fis1), and lower inflammatory cytokines. In vitro experiments in rat cardiomyocytes and fibroblasts showed reduced oxidative stress, fibroblast activation, proliferation, and migration. Exploratory RNA-sequencing suggested distinct mechanistic pathways. Key limitations include the small human cohort, the use of an animal model that may not fully replicate clinical AF, and the exploratory nature of mechanistic findings.
Biomedicines · May 2026DOI ↗ Animal only
This study investigated whether GHK-Cu (the tripeptide Glycine-Histidine-Lysine complexed with copper, naturally found in human plasma and urine) could delay aging using the roundworm Caenorhabditis elegans as a model organism. The researchers measured lifespan, stress resistance (oxidative and thermal), physical function (motility, pharyngeal pumping, defecation rhythm), and markers of cellular aging such as lipofuscin and lipid accumulation. They also examined mitochondrial health and key longevity signaling pathways. The study found that GHK-Cu extended worm lifespan, improved multiple age-related functional measures, and reduced aging biomarkers. At the mechanistic level, GHK-Cu appeared to preserve mitochondrial function—maintaining membrane potential, reducing age-related mitochondrial fragmentation, promoting mitochondrial fusion (via regulation of drp-1 and fzo-1), and increasing ATP production. Additionally, GHK-Cu activated the DAF-16 and SKN-1 longevity pathways and upregulated downstream target genes including sod-3, gst-4, gcs-1, lys-7, and lys-8. A key limitation is that all experiments were conducted in C. elegans; whether these findings translate to mammals or humans remains unknown.
Biogerontology · May 2026DOI ↗ Limited · humanPreprint
This large-scale observational study used an EHR-linked body-composition "digital phenotyping" pipeline — incorporating large language model (LLM)-based data extraction — to compare lean body mass (LBM) changes in routine clinical care among adults initiating GLP-1 receptor agonists (GLP-1RAs). Of 670,422 first-episode GLP-1RA users (456,742 on semaglutide; 213,680 on tirzepatide), 7,965 had paired pre- and post-initiation body-composition measurements analyzable over 12 months. The study found that tirzepatide was associated with greater relative LBM loss than semaglutide at each time point assessed (3, 6, 9, and 12 months), with excess LBM losses ranging from approximately 1.1% to 2.0%. The authors also identified two GLP-1 "metabotypes": a "Depletive" metabotype (>20% total body weight loss with >5% LBM loss), which was more frequent with tirzepatide (10.3%) than semaglutide (6.7%), and a "Prime" metabotype (>10% total body weight loss with preserved LBM). Key limitations include the observational, real-world design; reliance on LLM-extracted EHR data; potential unmeasured confounding; and the relatively small subset with paired body-composition data relative to the overall cohort.
Unknown journal · May 2026DOI ↗ Limited · human
This study investigated whether the synthetic peptide BPC 157 (Body Protection Compound-157) could relax human arterial tissue and whether that effect depends on the endothelium and nitric oxide (NO) signaling. Researchers used residual segments of internal mammary artery (IMA) collected from 12 patients undergoing elective coronary artery bypass graft surgery. Arterial rings were prepared with the endothelium either intact or deliberately removed, then pre-contracted with phenylephrine. Cumulative doses of BPC 157 were applied, and separate experiments used the NOS inhibitor L-NAME to assess NO involvement. The study found that BPC 157 produced a concentration-dependent reduction in arterial contraction in both endothelium-intact and endothelium-denuded rings, but relaxation was significantly greater when the endothelium was present. L-NAME pre-treatment blunted the relaxation response, implicating the endothelial NO pathway as the primary mechanism. Residual relaxation in denuded rings suggested that additional, endothelium-independent mechanisms also contribute. The authors acknowledge limitations including the small sample size (n = 12), the ex vivo nature of the tissue model, and the absence of in vivo or molecular mechanistic data, calling for further research before clinical conclusions can be drawn.
Journal of clinical medicine · May 2026DOI ↗ Review
This review traces the historical development and clinical adoption of FDA-approved drugs that incorporate d-amino acids — the non-natural mirror-image enantiomers of standard l-amino acids. The authors survey more than 20 FDA-approved drugs spanning therapeutic areas including infectious diseases, endocrine disorders, rare dermatologic conditions, and diagnostic imaging. Key examples discussed include naturally derived compounds such as gramicidin D and synthetic analogs including desmopressin, leuprolide, bremelanotide, and etelcalcetide — the latter highlighted as the first fully d-amino acid peptide to receive FDA approval. The review explains why d-amino acids are pharmacologically attractive: their resistance to proteolytic degradation, enhanced conformational rigidity, and reduced immunogenicity make them well-suited for long-acting and receptor-selective drug design. The authors also discuss enabling technologies, particularly solid-phase peptide synthesis and mirror-image phage display, that have accelerated the field. As a narrative review, the paper does not present new experimental data, conduct meta-analytic comparisons, or include a systematic literature search, which limits its ability to draw novel evidence-based conclusions. Its primary value lies in synthesizing the historical trajectory and mechanistic rationale of a growing drug class.
Drug development research · May 2026DOI ↗ Limited · human
This case report describes two adults living with well-controlled HIV-1 who presented with excess visceral abdominal fat (EVAF) under distinct clinical phenotypes. The first patient had a non-obese visceral adiposity phenotype (BMI 27 kg/m²) with increased waist circumference; treatment with tesamorelin, a growth hormone-releasing hormone analog, was associated with reductions in waist circumference, improved lipid levels, and enhanced functional well-being. The second patient had obesity (higher BMI) and received a GLP-1 receptor agonist; intermittent medication access led to fluctuating weight and persistent abdominal fat, after which the addition of tesamorelin was reported to provide more targeted visceral fat reduction. The authors argue that EVAF in people living with HIV can occur across BMI categories and may not be adequately captured by weight-based assessments alone. They conclude that individualized management informed by fat distribution patterns—rather than BMI or weight—is warranted. Key limitations include the single case-report design (n=2), absence of a control condition, lack of imaging-based visceral fat quantification reporting, and inability to draw generalizable conclusions about comparative efficacy.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · May 2026DOI ↗ Review
This paper is a commentary/review examining the rapidly evolving landscape of weight-loss pharmacotherapy, focusing on the progression from standard GLP-1 receptor agonists to dual and triple agonists capable of achieving 30–40% body weight reduction — outcomes previously only attainable through bariatric surgery. The authors argue that the pharmaceutical industry's competitive focus on maximizing weight-loss percentages is creating a disconnect between the metric of total body mass reduction and the broader goal of metabolic health. A central concern raised is that aggressive pursuit of high weight-loss targets may come at the cost of metabolic integrity and lean muscle mass preservation. The paper also touches on how escalating clinical benchmarks are influencing investor expectations and market dynamics. Notable limitations include the absence of primary data; the piece offers no original clinical trial results, relies on narrative argument rather than systematic evidence synthesis, and does not present a structured methodology for evaluating the compounds discussed. It does not provide specific dosing guidance but situates the debate within a broader physiological and economic context.
Molecules and cells · May 2026DOI ↗ Moderate · human
This network meta-analysis (NMA) synthesized evidence from six randomized controlled trials (N = 4,642; durations 12–68 weeks) to compare novel amylin-based therapies (ABTs) — amycretin, eloralintide, and cagrilintide/semaglutide (CagriSema) — against placebo and established anti-obesity agents (semaglutide 2.4 mg, liraglutide 3.0 mg) in adults with overweight or obesity without diabetes. Using a frequentist random-effects framework, the study found that high-dose subcutaneous amycretin produced the largest estimated reduction in percent body weight versus placebo (mean difference approximately −24%), followed by high-dose eloralintide (−18%) and high-dose CagriSema (−17%), all exceeding reductions seen with semaglutide 2.4 mg (−11%) and liraglutide 3.0 mg (−6%). Similar ranking patterns emerged for absolute weight, BMI, waist circumference, and categorical weight-loss thresholds. Gastrointestinal adverse events — particularly nausea, vomiting, and constipation — were more frequent with high-dose ABTs, and only high-dose CagriSema significantly increased treatment-discontinuation due to adverse events. The authors acknowledge that the included trials are few, relatively short-to-medium term, and carry low certainty of evidence, characterizing findings as preliminary and requiring confirmation in larger trials.
Endocrinology, diabetes & metabolism · May 2026DOI ↗ Moderate · human
This observational study used two target-trial emulations to compare cardiovascular outcomes among commercially insured U.S. adults with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) who initiated tirzepatide, dulaglutide, or semaglutide between June 2022 and December 2024. Using propensity-score (PS) 1:1 matching to reduce confounding, the researchers formed two cohorts: 9,233 tirzepatide–dulaglutide pairs and 25,266 tirzepatide–semaglutide pairs. The primary outcome was a modified MACE composite (nonfatal myocardial infarction, nonfatal stroke, and all-cause death). The study found that tirzepatide initiators had a statistically significantly lower rate of modified MACE compared with dulaglutide initiators (HR 0.80; 95% CI 0.65–0.99), largely driven by reduced all-cause mortality (HR 0.60; 95% CI 0.43–0.83); tirzepatide was also associated with fewer pneumonia-related hospitalizations versus dulaglutide. No significant difference in modified MACE was observed between tirzepatide and semaglutide initiators (HR 1.03; 95% CI 0.90–1.17). Key limitations include the observational design, potential residual confounding, reliance on administrative claims data, and a relatively short follow-up window.
Diabetes care · May 2026DOI ↗ Limited · human
This pharmacovigilance study used the U.S. FDA Adverse Event Reporting System (FAERS) database (Q2 2022–Q2 2025) to examine whether specific GLP-1 receptor agonists (GLP-1 RAs) — exenatide, lixisenatide, liraglutide, dulaglutide, semaglutide, and tirzepatide — differ in their association with alopecia and reproductive or endocrine-related adverse events. Researchers identified 1,276 alopecia-related and 759 reproductive/endocrine-related cases, then applied disproportionality analyses using crude and adjusted reporting odds ratios (cROR/aROR) from logistic regression, controlling for potential confounders. Sensitivity analyses with positive and negative control drugs were used to validate signal robustness. The study found that semaglutide was significantly associated with disproportionate reporting of alopecia (aROR 1.23) and several hormonal conditions, including polycystic ovary syndrome (aROR 6.59) and menstrual abnormalities. By contrast, dulaglutide and tirzepatide showed negative or non-significant associations for several reproductive outcomes. Important limitations include the inherent biases of spontaneous reporting systems (e.g., underreporting, notoriety bias, inability to establish causation), lack of denominator data, and absence of clinical detail. The authors conclude that agent-specific differences in endocrine and dermatologic safety profiles may warrant personalised prescribing decisions and ongoing surveillance.
Diabetes/metabolism research and reviews · May 2026DOI ↗ Review
This review examines the perioperative safety implications of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a drug class increasingly used for type 2 diabetes and obesity management. The authors focus on the mechanism by which GLP-1 RAs delay gastric emptying and how this pharmacological effect may elevate the risk of pulmonary aspiration during general anesthesia—specifically at induction and emergence—even when patients have followed standard preoperative fasting protocols. The review distinguishes between short-acting GLP-1 RAs, which reportedly cause more pronounced gastric emptying delays, and long-acting agents, whose residual effects may vary by dose and duration of treatment. The authors also survey updated guidance issued by international anesthesia societies in response to these concerns. Key limitations acknowledged include the overall scarcity and inconsistency of available clinical evidence. The review concludes by advocating for individualized, interdisciplinary perioperative management involving collaboration between endocrinologists and anesthesiologists. As a narrative review, it does not generate new primary data, and the conclusions are constrained by the quality of the underlying literature.
The Korean journal of internal medicine · May 2026DOI ↗ Review
This state-of-the-art review synthesizes available evidence on how glucagon-like peptide-1 receptor agonists (GLP-1 RAs) — drugs used for type 2 diabetes and weight management — affect blood pressure (BP). The authors examined data across populations including people with diabetes, obesity, and high cardiovascular risk. The review reports that GLP-1 RAs are associated with modest systolic BP reductions, typically in the range of 2–5 mm Hg, which the authors attribute primarily to weight loss, with potential additional contributions from weight-independent mechanisms such as natriuresis (increased urinary sodium excretion), improved endothelial function, and reduced vascular inflammation. The review notes that while these reductions are smaller than those achieved with traditional antihypertensive medications, they may translate to meaningful cardiovascular risk reduction at a population level and may offer additive benefit alongside conventional therapies. The authors also highlight that small increases in heart rate and possible interactions with volume-regulating medications may require clinical monitoring. Limitations acknowledged include the indirect and heterogeneous nature of the synthesized evidence. The review concludes by calling for further research as newer GLP-based therapies emerge to better inform integrated cardiometabolic care strategies.
American journal of hypertension · May 2026DOI ↗