Daily Endocrinology Research Analysis

BACKGROUND: Preparation for radioiodine (RAI) therapy in differentiated thyroid cancer (DTC) often requires thyroid hormone withdrawal (THW) to achieve thyrotropin (TSH) stimulation. Current guidelines recommend TSH ≥30 mIU/L, a target that prolongs hypothyroidism and worsens quality of life, yet rests on limited evidence. OBJECTIVE: To evaluate the association between pre-RAI TSH levels and oncologic outcomes in adults with DTC prepared by THW. METHODS: We conducted a systematic review and meta-analysis of studies comparing outcomes across pre-RAI TSH thresholds (<30 vs. ≥30, <60 vs. ≥60, and <90 vs. ≥90 mIU/L) in adults with DTC prepared by THW. Primary outcomes included disease-specific mortality, recurrence, and response to therapy. Searches in MEDLINE, Embase, Cochrane, and Scopus (inception to March 2025) identified eligible studies. Risk of bias was assessed using the CLARITY tool and certainty of evidence using GRADE. Pooled relative risks (RRs) were calculated using random-effects models. This systematic review was registered in PROSPERO (CRD42020158354). RESULTS: This meta-analysis included eight retrospective cohort studies comprising a total of 4651 DTC patients, predominantly women (68.5%) with a mean age of 46 years. All patients underwent THW before RAI. Across all TSH thresholds examined (<30, <60, and <90 mIU/L), higher pre-RAI TSH levels were not associated with better treatment response, lower recurrence, or reduced mortality. Specifically, patients with higher pre-RAI TSH levels (≥30 mIU/L) did not have better oncologic outcomes compared with those with lower levels (<30 mIU/L). At 2- and 3-year follow-up, no significant differences were observed in excellent (pooled RR = 0.87; confidence interval [CI] 0.68-1.11) or indeterminate (RR = 1.28; CI 0.72-2.27) response rates. Similarly, recurrence rates did not differ (RR = 1.45; CI 0.83-2.55), and no study demonstrated a difference in disease-specific mortality across follow-up periods extending up to 10 years. The certainty of evidence for all outcomes was rated very low due to risk of bias, heterogeneity, and imprecision. CONCLUSIONS: The current evidence base is insufficient to support or refute the routine use of a specific TSH threshold before RAI administration. These findings question the recommendation to achieve TSH ≥30 mIU/L before RAI and highlight the need for trials to define the minimal effective level of TSH stimulation.

IMPORTANCE: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are considered safe, effective medications for type 2 diabetes (T2D) and weight loss, used by millions worldwide. While their cardiometabolic benefits are well established, emerging observations suggest a potential association between GLP-1RA use and new-onset nonarteritic anterior ischemic optic neuropathy (NAION). OBJECTIVE: To emulate a target trial evaluating the risk of NAION associated with initiation of semaglutide (GLP-1RA), compared with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) as second-line therapy for T2D in a nationwide cohort of US veterans. DESIGN, SETTING, AND PARTICIPANTS: This study was conducted nationwide using data from the Veterans Health Administration health care system between March 1, 2018, and March 1, 2025. This active-comparator, new-user, target trial emulation used cause-specific hazard ratios (HRs) that were estimated using overlap weighting to account for confounding. Participants included US veterans with T2D, current metformin use, and no prior GLP-1RA or SGLT2i use. Data analysis was conducted from July 2025 through September 2025. EXPOSURE: Initiation of semaglutide or any SGLT2i. MAIN OUTCOME AND MEASURE: Incident NAION, identified using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision and Systematized Nomenclature of Medicine codes. RESULTS: A total of 102 361 US veterans met inclusion criteria, including 11 478 initiators of semaglutide and 90 883 initiators of an SGLT2i. Baseline characteristics were well balanced between treatment groups after overlap weighting (mean [SD] age, 60.1 [11.7] years; body mass index, 37.8 [6.7]; hemoglobin A1c, 7.0% [1.4]; 85.5% male and 14.5% female; 20.7% Black, 8.1% Hispanic, and 61.9% non-Hispanic White). Over a maximum follow-up of 7.5 years, 173 total incident NAION events occurred. The incidence rate of NAION was 123 per 100 000 person-years among semaglutide initiators and 67 per 100 000 person-years among SGLT2i. In 2.1 years of median follow-up, semaglutide initiators had a 2.33-fold higher risk than SGLT2i initiators (hazard ratio, 2.33; 95% CI, 1.54-3.54; P < .001). The overlap weighted incidence rate of NAION was 0.29% for semaglutide initiators and 0.13% for SGLT2i initiators, with a corresponding average treatment effect of 0.16 percentage points. CONCLUSIONS AND RELEVANCE: In this nationwide cohort of US veterans with T2D, semaglutide initiators had a 2-fold NAION risk than SGLT2i initiators, while the absolute risk was low. Clinicians and patients should be counseled on the rare but evident increased risk of NAION after semaglutide initiation.

CONTEXT: Smoking is a recognised risk factor for Graves' disease (GD), but its quantitative relationship with disease severity, autoimmunity, and relapse after antithyroid drug (ATD) therapy is unclear. OBJECTIVE: To evaluate the dose-dependent association between smoking exposure and key clinical outcomes in GD. DESIGN: Observational cohort study. SETTING: Single-centre secondary-care endocrinology service in the United Kingdom. PATIENTS: Consecutive adults with newly diagnosed GD confirmed by suppressed TSH, elevated thyroid hormones, and positive TRAb or diffusely increased scintigraphic uptake. All 991 eligible patients were included in baseline analyses; 663 completed ≥12 months follow-up after ATD cessation, and 712 contributed to long-term relapse analyses. MAIN OUTCOME MEASURES: Baseline TRAb and thyroid hormone levels, symptom score, presence of orbitopathy, ATD duration, and relapse at 12 months and long term, defined as recurrent biochemical hyperthyroidism with elevated TRAb after ATD withdrawal. Exposures were smoking status (non-, ex-, current smoker) and cigarettes/day. RESULTS: Current smokers (27%) had higher TRAb levels at diagnosis (median 7.8 vs 6.6 IU/L in non-smokers, p=0.002) and increased odds of orbitopathy (OR 1.76, 95% CI 1.17-2.64). Each 10 cigarettes/day conferred a 34% (95% CI 10-79%) higher odds of orbitopathy and 60% higher 12-month relapse risk. Smokers also had higher TRAb at ATD cessation. In time-dependent Cox models, excess relapse risk among current smokers was greatest early after ATD withdrawal (HR 1.24 at 6 months) and diminished by 2 years. TRAb mediated only 7% of the smoking-relapse association. CONCLUSIONS: Smoking is associated with greater autoimmune activity, higher orbitopathy risk, and increased relapse in a dose-dependent manner. Ex-smokers have risks comparable with non-smokers, supporting cessation or reduction as a meaningful intervention to improve GD outcomes.