This Week in Peptide Research: Orforglipron Dosing Data, GLP-1 Safety Signals, and a Teriparatide-Osteosarcoma Reporting Signal

Peptide Science Daily reviewed new PubMed listings for its tracked compounds from September 13 through September 20, 2026. It was a busy week with no single dominant story but a heavy volume of GLP-1 and amylin-receptor literature, alongside bone-peptide safety data, two LL-37 papers, and a cluster of somatostatin-analog, GLP-2, and bleeding-disorder studies.

Two papers examined orforglipron, the oral non-peptide GLP-1 receptor agonist approved by the FDA in April 2026 as Foundayo for chronic weight management, dosing and long-term risk projections. A meta-analysis in BMC Endocrine Disorders pooled six randomized controlled trials (3,459 participants) comparing orforglipron's two most-studied maintenance doses. The 36 mg dose produced significantly greater reductions than the 12 mg dose in body weight, BMI, HbA1c, waist circumference, triglycerides, and systolic blood pressure (all p<0.00001 to p=0.002), with comparable rates of adverse events and gastrointestinal side effects between doses, though the 36 mg dose was linked to small increases in liver enzymes ALT and AST that the authors said were not clinically significant at the doses and durations tested. Separately, in Diabetes, Obesity and Metabolism, an Eli Lilly-funded post hoc analysis of the Phase 3 ATTAIN-1 trial applied three validated risk-prediction models to 72-week trial data from adults with overweight or obesity without type 2 diabetes. Orforglipron was associated with significantly larger reductions in predicted 10-year risk of type 2 diabetes (48.6% to 59.4% relative reduction versus 10.5% with placebo, p<0.0001) and of cardiovascular disease using both the Framingham and PREVENT risk engines (p<0.0001 for each). The authors described this as a projection based on validated risk models, not a measured reduction in actual disease events.

Two papers compared GLP-1-family drugs against each other. In Diabetes, Metabolism Syndrome and Obesity, a systematic review and meta-analysis of eight randomized trials (6,898 participants) found CagriSema, Novo Nordisk's combination of semaglutide and the investigational amylin analog cagrilintide, produced significantly greater percentage body weight loss than semaglutide alone (mean difference -6.60%), cagrilintide alone (-8.15%), and placebo (-14.30%), along with greater HbA1c reduction, though with more gastrointestinal adverse events than any comparator and substantial statistical heterogeneity between trials. Separately, in iScience, a Chinese team compared semaglutide, tirzepatide, and retatrutide, all three approved or investigational GLP-1-family drugs, in mouse models of non-diabetic kidney fibrosis (surgical ureter obstruction and natural aging). Retatrutide showed the greatest anti-fibrotic effect at the doses tested, acting through simultaneous inhibition of two distinct inflammatory signaling pathways, while the other two drugs each worked through a subset of those pathways. The authors called the results hypothesis-generating rather than clinically established, since the models are not diabetic and translation to human kidney disease is untested.

Several papers this week examined safety and patient experience with GLP-1 and MC4R-agonist obesity drugs. A meta-analysis in World Journal of Methodology pooled seven studies (237 men) on GLP-1 receptor agonists and erectile function, and found active treatment was associated with significantly improved erectile-function scores and higher total testosterone, sex-hormone-binding globulin, and follicle-stimulating hormone, with no significant change in free testosterone or luteinizing hormone; the authors said larger randomized trials are needed and did not report evidence of GLP-1 drugs causing impotence. A case series in JCEM Case Reports described two women who developed multiple simultaneous eyelid gland cysts (hordeola progressing to chalazia) after starting tirzepatide, an approved dual GLP-1/GIP receptor agonist; in one patient symptoms recurred on rechallenge after resolving off the drug, which the single-author case series described as strong evidence of a causal link in that patient, while cautioning this is a first-reported association based on two cases. In Diabetes Therapy, an Eli Lilly-funded qualitative study conducted exit interviews with 74 of 147 invited participants who completed the multiyear SURPASS-CVOT trial on dulaglutide or tirzepatide for type 2 diabetes with cardiovascular disease; most reported meaningful benefits including improved glycemic control (97.3%), weight loss (91.9%), and reduced appetite (78.4%), with nausea the most common adverse event (28.4%) and most participants saying they would recommend their treatment. A related discrete-choice study funded by Novo Nordisk, surveying 800 US adults with obesity or overweight, found route of administration, weight-loss efficacy, and cardiovascular risk reduction were the top-ranked factors in hypothetical obesity-drug choices, with participants favoring a semaglutide-like injectable profile over an orforglipron-like oral profile in the scenarios tested. Separately, a case report and literature review in Nephron described a 37-year-old man with Bardet-Biedl syndrome whose metabolic and kidney markers improved further after switching from liraglutide to setmelanotide, an MC4R agonist approved for obesity in that syndrome; the authors noted supporting evidence remains limited to this case and two small interventional studies.

Bone-forming peptide safety was a second major thread. In Pharmacological Reports, a pharmacovigilance study analyzed FDA Adverse Event Reporting System data through February 2025 and found 29 osteosarcoma reports among teriparatide's 112,798 total adverse-event reports, a disproportionately high reporting rate compared with all other drugs combined (reporting odds ratio 15.31, 95% CI 10.53-22.26), a signal that held when restricted to reports since 2006. However, the same disproportionality signal did not appear when teriparatide was compared specifically against romosozumab, another osteoporosis drug, rather than against all drugs generally. The authors said this pattern, combined with prior evidence not supporting a real increased risk, means the finding warrants further research rather than a change in clinical practice; FAERS reporting-rate analyses cannot establish that a drug caused the reported events. Separately, in JCEM Case Reports, clinicians described two patients with rare medication-related osteonecrosis of the external auditory canal linked to more than a decade of bisphosphonate or denosumab therapy; an 8-week and a 4-month course of teriparatide, respectively, brought symptomatic and biochemical improvement in both, but CT imaging did not fully normalize in either patient, and one required surgery. A broader evidence review in Calcified Tissue International mapped anti-osteoporotic drugs, including teriparatide, abaloparatide, denosumab, and romosozumab, for effects on muscle mass and strength in osteosarcopenia, and concluded that none has a randomized clinical evidence base strong enough for pooled analysis, with denosumab's bone-density benefit not translating into measured muscle gains in long-term-care patients. In a fourth bone paper, a Sichuan University team reported in the Journal of Materials Chemistry B that abaloparatide encapsulated in a photothermally triggered hydrogel improved bone regeneration in a cranial defect model in animals, a delivery-engineering result, not a human clinical finding.

Two papers advanced LL-37, an investigational human antimicrobial peptide with no FDA, EMA, or TGA approval. A narrative review in Odontology examined why LL-37, despite strong preclinical and mechanistic data in oral disease, has seen little clinical translation, citing proteolytic degradation, cytotoxicity at higher concentrations, rapid salivary clearance, and high production costs as barriers, and proposed peptide engineering, nanocarrier delivery, and vitamin D-mediated induction of the body's own LL-37 as future directions. Separately, in Histology and Histopathology, a Chinese team reported that LL-37 suppressed viability, blood-vessel formation, and metastatic spread of gastric cancer cells in culture and in a mouse xenograft model, acting by blocking the NF-kB signaling pathway and lowering downstream inflammatory and vessel-growth signals; the authors described this as a rationale for further study of LL-37 as a candidate therapeutic in gastric cancer, based on laboratory and animal data rather than any clinical testing.

Several other papers concerned approved somatostatin-analog, GLP-2, and bleeding-disorder drugs. In Pediatric Research, a multicenter registry following 140 children with intestinal failure found teduglutide, a GLP-2 analog with a pediatric approval dating to 2019, was associated with a progressive and sustained reduction in intravenous nutrition needs, from an 8.3% mean reduction in parenteral calories at 6 months to 49.5% at 3 years, while the modeled proportion of children with low weight-for-age scores rose from 2.3% to 12.7% over the same period, which the authors said warrants careful nutritional monitoring rather than signaling a safety failure. In Haemophilia, a retrospective study of 170 children with von Willebrand disease found that two different published systems for classifying response to a desmopressin (DDAVP) challenge disagreed substantially, rating 59% versus 81% of children as complete responders depending on which criteria were applied, and that response was best predicted by a child's baseline clotting-factor activity level rather than by age or blood type. Octreotide, an approved somatostatin analog, featured in two papers: a Chinese team built a machine-learning model using dual-tracer PET/CT imaging in 32 patients that predicted which liver metastases from neuroendocrine tumors would respond to octreotide, with an accuracy up to 79% in cross-validation, and an Egyptian team found octreotide reduced kidney injury markers in rats given the chemotherapy drug cisplatin, with protection strongest when octreotide was given both before and after the cisplatin dose. A clinical review in the Journal of Clinical Endocrinology and Metabolism outlined a biomarker-guided approach to choosing between somatostatin analogs, pegvisomant, and pasireotide in acromegaly, reporting that a validated strategy could help identify patients unlikely to respond to first-line drugs earlier and had been associated with hormonal control in nearly 80% of patients in the study it was based on.

Two smaller items rounded out the week. A review in the Journal of Bioenergetics and Biomembranes examined mitokines, cell-signaling factors released during mitochondrial stress, in cardiovascular disease, covering the mitochondrial-derived peptides humanin and MOTS-c alongside two non-peptide factors; the author proposed that patterns across multiple mitokines, rather than any single one, may eventually inform cardiovascular risk assessment, while noting major mechanistic gaps remain, particularly for the peptide signals. Humanin has no FDA, EMA, or TGA approval, and MOTS-c is prohibited at all times under WADA's metabolic-modulator category with no therapeutic-use exemption available. Separately, a Turkish research team reported in the Journal of Molecular Histology that hexarelin, an investigational growth-hormone secretagogue, reduced pancreatic tissue damage and inflammation in a mouse model of Parkinson's-disease-associated toxicity, though the authors cautioned that one treatment-timing arm lacked a matched control needed to fully separate the drug's effect from the passage of time.

This week's items span two dose-comparison and outcome-projection analyses in humans, two animal or cell-culture comparative pharmacology studies, four bone-safety papers including one pharmacovigilance signal, two LL-37 papers, and a cluster of somatostatin-analog, GLP-2, and bleeding-disorder studies, several industry-funded. Orforglipron, semaglutide, tirzepatide, dulaglutide, liraglutide, teriparatide, abaloparatide, octreotide, teduglutide, desmopressin, and setmelanotide are approved drugs, though orforglipron's approval is limited to the FDA and to weight management. Cagrilintide, retatrutide, LL-37, hexarelin, and humanin remain investigational with no FDA, EMA, or TGA approval, and MOTS-c is WADA-prohibited at all times. The teriparatide-osteosarcoma FAERS signal and the tirzepatide eyelid case series are both early, unconfirmed safety observations, not established adverse effects. As with all research covered here, these are findings a given study reported, not established clinical fact or treatment guidance.