Marked and reversible circulating insulin-like growth factor-1 elevation during teprotumumab N01 treatment for thyroid eye disease with limited correspondence to glycemic changes
Teprotumumab N01 treatment was associated with a substantial, early, and broadly reversible increase in circulating IGF-1 in patients with moderate-to-severe TED, but IGF-1 dynamics did not serve as an independent indicator of glycemic deterioration.
Abstract
Background Insulin-like growth factor-1 (IGF-1) receptor (IGF-1R) inhibitors have changed the treatment landscape for moderate-to-severe thyroid eye disease (TED), but the longitudinal behavior of circulating IGF-1 during and after therapy remains insufficiently characterized. This study aimed to describe serum IGF-1 dynamics in patients with TED treated with IGF-1R inhibitor teprotumumab N01 and to explore their relationship with glycemic changes. Methods In this retrospective cohort study, 92 patients with moderate-to-severe TED treated with teprotumumab N01 who had longitudinal IGF-1 measurements were included. IGF-1 dynamics were characterized at infusion-based visits and during post-treatment follow-up. Glycemic changes were assessed using fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and glycated albumin (GA). Patients were classified by baseline glycemic status. Associations between IGF-1 metrics and glycemic changes were evaluated using multivariable linear regression for continuous glycemic outcomes and logistic regression for threshold-defined glycemic events, with sequential adjustment for age, sex, baseline glycemic markers, and baseline IGF-1 when applicable. Additional analyses were performed according to baseline glycemic status and baseline HbA1c quartiles. Results Baseline serum IGF-1 was 151.0 ng/mL (IQR 116.8–187.3). IGF-1 increased markedly after treatment initiation, with a median early-treatment peak fold change of 3.5 (IQR 3.0–4.3) and a median on-treatment peak concentration of 649.5 ng/mL (IQR 520.8–753.8), corresponding to a 4.2-fold increase from baseline (IQR 3.5–5.0). IGF-1 remained elevated during the first 3 months after the last infusion and then declined progressively, generally approaching baseline by 6–9 months or later. Glycemic markers showed modest increases, with median peak increases from baseline of 0.40% (IQR 0.20–0.77) for HbA1c, 1.63% (IQR 0.95–2.39) for GA, and 0.65 mmol/L (IQR 0.30–1.14) for FBG. Glycemic deterioration was most pronounced in patients with baseline dysglycemia. In contrast, neither baseline IGF-1 nor IGF-1 dynamic metrics were consistently identified as independent correlates of glycemic changes after adjustment for age, sex, and baseline glycemic markers and IGF-1. Similar findings were observed in subgroup and HbA1c quartile analyses. Conclusion Teprotumumab N01 treatment was associated with a substantial, early, and broadly reversible increase in circulating IGF-1 in patients with moderate-to-severe TED, but IGF-1 dynamics did not serve as an independent indicator of glycemic deterioration.
Findings indicate significant changes in the IGF system in patients with T1D, and changes in IGF-1 and IGF-2 levels are thought to be related to the metabolic disturbances seen in T1D.
E. M. Eltayef, K. Gharab, L. Ghannawi et al.· Diabetes mellitus· 0 citations
Abstract Teprotumumab, an insulin-like growth factor-1 (IGF-1) receptor antibody, has been approved for thyroid eye disease (TED) treatment. However, teprotumumab is associated with adverse events such as hyperglycemia, and the underlying mechanisms of teprotumumab-related hyperglycemia remain unclear. We report a case of teprotumumab-related hyperglycemia with endocrinological evaluation. A 60-year-old woman with Graves disease developed active TED and was treated with teprotumumab. The patient had preexisting type 2 diabetes managed with oral hypoglycemic agents. At 6 weeks after teprotumumab initiation, glycemic control deteriorated, necessitating temporary teprotumumab discontinuation and insulin therapy initiation. Serum growth hormone (GH) level changed minimally, whereas serum IGF-1 level increased markedly, suggesting increased integrated GH secretion. Fasting plasma glucose level substantially increased, whereas serum immunoreactive insulin level only modestly increased, indicating insufficient endogenous insulin secretion. Following glycemic improvement with insulin therapy, teprotumumab was resumed, and 8 infusions were completed. Despite persistently elevated serum IGF-1 levels, insulin was gradually tapered with concomitant weight loss and was discontinued at 9 weeks after the final infusion. In patients with reduced endogenous insulin secretory capacity, teprotumumab-related hyperglycemia may develop when endogenous insulin secretion is insufficient to compensate for GH-mediated increases in hepatic gluconeogenesis and insulin resistance.
Ken Sugawa, Yuji Hataya, Kimiaki Murabe et al.· JCEM Case Reports· 1 citation
Elevated IGF-1 levels in CSCR patients suggest that this growth factor may contribute to disease pathogenesis through mechanisms involving choroidal vascular permeability and retinal endothelial activity.
Naciye Tora, Gunhal Satırtav, Filiz Alkan Baylan et al.· Ophthalmic Surgery Lasers an...· 0 citations
OBJECTIVE
To explore whether the favorable association between weight loss and glycemic improvement in patients with obesity and type 2 diabetes mellitus (T2DM) is partially mediated by weight loss-induced changes in the hypothalamic-pituitary-thyroid (HPT) axis, including alterations in thyroid-stimulating hormone (ΔTSH), free triiodothyronine (ΔFT3), and free thyroxine (ΔFT4).
METHODS
A total of 364 patients with obesity and T2DM who underwent bariatric surgery, glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy, or standardized lifestyle intervention were enrolled in this retrospective real-world cohort study. Anthropometric, glycemic, and thyroid function indicators were measured at baseline and after a median follow-up of approximately 12 months.
RESULTS
Weight loss interventions led to significant reductions in body weight, glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and homeostatic model assessment for insulin resistance (HOMA-IR), as well as a significant increase in homeostatic model assessment for β-cell function (HOMA-β) (all P < 0.001). Serum TSH and FT3 levels decreased markedly after intervention (both P < 0.001), whereas FT4 levels remained stable (P = 0.542). Changes in TSH and FT3 were significantly correlated with changes in HbA1c (ΔTSH: r = 0.319, P < 0.001; ΔFT3: r = 0.135, P = 0.010). The HPT axis exerted a significant total indirect mediating effect of 10.7% on the association between weight loss and HbA1c improvement (P = 0.032), with ΔTSH contributing 5.5% and ΔFT3 contributing 5.2% of the total effect. Subgroup analysis showed that the indirect mediating effect was more prominent in patients with higher baseline TSH levels.
CONCLUSION
Changes in thyroid axis markers, specifically reductions in TSH and FT3, significantly and indirectly mediate the improvement in glycemic control following weight loss interventions in T2DM patients. Although this mediating effect is modest in overall magnitude, it is augmented in individuals with elevated baseline TSH levels. These findings suggest a novel auxiliary mechanism underlying the metabolic benefits of weight loss mediated by HPT axis remodeling.
Peng Li, Jingjing Zhang, Meiqi Li· American journal of translat...· 0 citations
Background: Type 2 diabetes mellitus is commonly associated with obesity, metabolic liver disease, and chronic low-grade inflammation. Semaglutide is known to improve glycaemic control and body weight, but its real-world associations with hepatic markers, fibrosis-related indices, and systemic inflammatory parameters remain incompletely characterized. This study evaluated changes in metabolic, hepatic, and inflammatory parameters during injectable semaglutide treatment and explored whether these changes differed according to baseline disease status. Methods: A retrospective observational study was conducted in patients with type 2 diabetes treated with injectable semaglutide 1 mg/week and followed for six months. Anthropometric, metabolic, hepatic, and inflammatory variables were collected at baseline and follow-up, including liver enzymes, the Fibrosis-4 (FIB-4) index, and the systemic immune–inflammation (SII) index. Analyses included correlation analyses and exploratory stratification according to baseline fibrosis risk and inflammatory status. Results: Semaglutide treatment was associated with significant reductions in body weight, body mass index, fasting glucose, HbA1c, and triglyceride levels. Alanine and aspartate aminotransferase levels decreased significantly, consistent with a reduction in liver enzyme abnormalities during follow-up. No significant overall changes were observed in FIB-4, an indirect fibrosis-related index, or in SII, an indirect hematological inflammatory index. However, exploratory stratified analyses suggested that patients with higher baseline FIB-4-estimated fibrosis risk or elevated SII values showed greater reductions in these indices, whereas those with low baseline risk showed no relevant changes. Conclusions: In routine clinical practice, six months of injectable semaglutide treatment was associated with favorable metabolic changes and reductions in liver transaminases in patients with type 2 diabetes mellitus. Findings related to FIB-4 and SII should be interpreted cautiously, as these are indirect indices and the baseline-dependent patterns observed were exploratory and hypothesis-generating.
R. García-Pérez, V. Siles-Guerrero, Aida Elhadri-Egea et al.· Endocrines· 0 citations
Purpose: To investigate the effect of dapagliflozin combined with metformin on metabolic, oxidative and endothelial factors, with a particular focus on sex-specific variation.Methods: A total of 32 patients (18 males, 14 females) were recruited from Al-Salam Teaching Hospital in Mosul city, Iraq. The patients received metformin monotherapy (1000 mg/day) from October 2024 to April 2025. Thereafter, dapagliflozin (10 mg/day) was administered as an adjuvant therapy for 8 weeks. Serum samples were collected before and 8 weeks after dapagliflozin therapy, and HbA1c, total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), malondialdehyde (MDA), total antioxidant status (TAS), vascular and intercellular cell adhesion molecule 1 (VCAM-1 and ICAM-1) were measured using enzyme-linked immunosorbent assay (ELISA).Results: Dapagliflozin therapy significantly reduced glycated haemoglobin (HbA1c), cholesterol, LDL, and atherogenic index, with a significant reduction of TG in males compared to females (p < 0.05). Serum MDA was significantly reduced in both sexes (p < 0.01), while TAS was significantly higher in females compared to males (p < 0.001). Furthermore, VCAM-1 and ICAM-1 did not significantly change in either sex.Conclusion: Treatment with dapagliflozin following metformin therapy induced favourable hypolipidemic and oxidative benefits with sex-related differences, which highlighted the importance of considering biological sex when evaluating antidiabetic agents.
Hani M. Almukhtar, Adil M. Najm, S. H. Othman· Tropical Journal of Pharmace...· 0 citations
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