Endocrinology and Metabolism

Articles in E-pub version are posted online ahead of regular printed publication.

Original Articles

Medullary Thyroid Carcinoma Detected by Routine Health Screening Had Better Clinical Outcome and Survival: Ji Hyun Yoo, Da Eun Leem, Bo Ram Kim, Tae Hyuk Kim, Sun Wook Kim, Jae Hoon Chung; Received October 22, 2024 Accepted January 8, 2025 Published online March 5, 2025; DOI: https://doi.org/10.3803/EnM.2024.2214 [Epub ahead of print]

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Abstract PDF: Background
The benefits of early detection in medullary thyroid carcinoma (MTC) are not well established. This study investigates the impact of early detection of MTC on clinical outcomes.
Methods
This retrospective study evaluated 144 patients diagnosed with MTC at Samsung Medical Center between 1995 and 2019, classified as asymptomatic (mostly detected through routine health check-ups, including ultrasonography, calcitonin, or carcinoembryonic antigen levels) and symptomatic. Initial treatment response, final clinical outcomes, and cancer-specific survival were compared.
Results
MTC was diagnosed in 104 (72.2%) asymptomatic and 40 (27.8%) symptomatic patients. The symptomatic group showed a significantly larger primary tumor size, more frequent lateral neck lymph node metastasis, more advanced tumor, node, metastasis (TNM) staging, and higher pre- and postoperative serum calcitonin levels. For initial treatment response, the proportion of excellent responders was significantly higher in the asymptomatic group (71.2% vs. 40.0%), while that of patients with biochemical incomplete response (37.5% vs. 26.9%) and structural incomplete response (22.5% vs. 1.9%) was significantly higher in the symptomatic group (all P<0.001). For the final clinical outcomes, the rate of patients with no evidence of disease was higher in the asymptomatic group (67.3% vs. 30.0%), while the rate of patients with structurally identifiable disease was higher in the symptomatic group (45.0% vs. 7.7%) (P<0.001 for both). The symptomatic group had significantly poorer cancer-specific survival than the asymptomatic group (log-rank P=0.023).
Conclusion
Compared with late diagnosis through symptomatic presentation, early diagnosis in asymptomatic patients results in significantly better initial treatment response, final clinical outcomes, and cancer-specific survival in patients with MTC.

Association between the Triglyceride-Glucose Index and Cardiovascular Risk and Mortality across Different Diabetes Durations: A Nationwide Cohort Study: Jeongeun Kwak, Kyung-Do Han, Eun Young Lee, Seung-Hwan Lee, Dong-Jun Lim, Hyuk-Sang Kwon, Jeongmin Lee; Received October 15, 2024 Accepted January 3, 2025 Published online March 5, 2025; DOI: https://doi.org/10.3803/EnM.2024.2205 [Epub ahead of print]

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Abstract PDF: Background
We aimed to assess the association between triglyceride-glucose (TyG) index and cardiovascular disease (CVD) risk and mortality in a large cohort of diabetes patients.
Methods
A retrospective cohort study of 1,090,485 participants from the Korean National Health Insurance Service database was conducted. Participants were stratified into TyG quartiles.
Results
Higher TyG index quartiles were significantly associated with an increased CVD risk and mortality risk. In fully adjusted models, participants in the highest TyG quartile (Q4) had an 18% higher risk of CVD (hazard ratio [HR], 1.18; 95% confidence interval [CI], 1.13 to 1.23) and a 16% higher risk of mortality (HR, 1.16; 95% CI, 1.11 to 1.23) compared to those in the lowest quartile (Q1). The association was particularly pronounced in patients with fasting glucose ≥126 mg/dL (CVD [HR, 1.33; 95% CI, 1.29 to 1.37], mortality [HR, 1.23; 95% CI, 1.20 to 1.26]; P for interaction <0.001). Patients with a diabetes duration of ≥10 years showed the strongest association between the TyG index and CVD risk (HR, 1.44; 95% CI, 1.38 to 1.50), while the mortality risk was particularly elevated in those with a diabetes duration of less than 5 years (HR, 1.23; 95% CI, 1.18 to 1.30). Subgroup analyses revealed stronger associations between TyG index and CVD risk in younger participants, non-obese individuals, and non-smokers.
Conclusion
The TyG index is a significant predictor of CVD and mortality in diabetic patients, particularly in those with poor glycemic control or longer disease duration.

Plasma C-Peptide Levels and the Continuous Glucose Monitoring-Defined Coefficient of Variation in Risk Prediction for Hypoglycemia in Korean People with Diabetes Having Normal and Impaired Kidney Function: So Yoon Kwon, Jiyun Park, So Hee Park, You-Bin Lee, Gyuri Kim, Kyu Yeon Hur, Jae Hyeon Kim, Sang-Man Jin; Received July 2, 2024 Accepted November 13, 2024 Published online February 27, 2025; DOI: https://doi.org/10.3803/EnM.2024.2083 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
We aimed to investigate the predictive values of plasma C-peptide levels and the continuous glucose monitoring (CGM)-defined coefficient of variation (CV) in risk prediction for hypoglycemia in Korean people with diabetes with normal and impaired kidney function.
Methods
We analyzed data from 1,185 participants diagnosed with type 1 and type 2 diabetes who underwent blinded professional CGM between January 2009 and May 2021 at outpatient clinics. We explored correlations among CGM-defined CV, plasma C-peptide levels, and time below range at <70 and 54 mg/dL across different kidney function categories.
Results
In patients with chronic kidney disease (CKD) stages 1–2 (n=934), 89.3% who had a random plasma C-peptide level higher than 600 pmol/L exhibited a CV of ≤36%. Among those in CKD stage 3 (n=161) with a random plasma C-peptide level exceeding 600 pmol/L, 66.7% showed a CV of ≤36%. In stages 4–5 of CKD (n=90), the correlation between random C-peptide levels and CV was not significant (r=–0.05, P=0.640), including cases with a CV greater than 36% despite very high random plasma C-peptide levels. Random plasma C-peptide levels and CGM-assessed CV significantly predicted hypoglycemia in CKD stages 1–2 and 1–5, respectively.
Conclusion
The established C-peptide criteria in Western populations are applicable to Korean people with diabetes for hypoglycemic risk prediction, unless kidney function is impaired equivalent to CKD stage 3–5. The CGM-defined CV is informative for hypoglycemic risk prediction regardless of kidney function.

Microvascular Ultrasonography Vascularity Index as a Rapid and Simplified Assessment Tool for Differentiating Graves’ Disease from Destructive Thyroiditis and Managing Thyrotoxicosis: Han-Sang Baek, Chaiho Jeong, Jeonghoon Ha, Dong-Jun Lim; Received October 12, 2024 Accepted December 2, 2024 Published online February 25, 2025; DOI: https://doi.org/10.3803/EnM.2024.2206 [Epub ahead of print]

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Abstract PDF PubReader ePub: Background
Thyrotoxicosis presents significant diagnostic challenges in distinguishing Graves’ disease (GD) from destruction-induced thyrotoxicosis (DT) using ultrasound imaging. We evaluated a new technology, microvascular ultrasonography (MVUS) to effectively differentiate between GD and DT, and observe the MVUS changes during follow-up.
Methods
A total of 264 consecutive patients were prospectively enrolled into two cohorts from August 2022 to March 2024 at one tertiary referral hospital: cohort 1 comprised patients initially presenting with thyrotoxicosis (n=185; 98 with GD and 87 with DT). Cohort 2 included patients either with GD considering antithyroid drug discontinuation or with DT in the follow-up phase after treatment (n=77). Ultrasound imaging was conducted using the MVUS technique, and the vascularity index (MVUS-VI) was automatically calculated as the percentage ratio of color pixels to total grayscale pixels within a specified region of interest.
Results
Diagnostic accuracy highlighted MVUS-VI as the most accurate diagnostic tool, achieving a sensitivity of 79.6%, specificity of 84.3%, with an area under the curve of 0.856 (95% confidence interval, 0.800 to 0.911). Presence of thyroid peroxidase antibody or thyroglobulin antibody affected MVUS-VI’s performance, requiring a higher cut-off value for specificity in this subgroup. Follow-up in cohort 2 (n=77) demonstrated significant normalization in thyroid function and reductions in MVUS-VI from an initial 32.6%±23.4% to 20.8%±13.5% at follow-up (P<0.001).
Conclusion
MVUS-VI provides a rapid, non-invasive diagnostic alternative to traditional methods in differentiating GD from DT, thus aiding in the management of patients with thyrotoxicosis.

Prognostic Impact of Primary Tumor Size in Papillary Thyroid Carcinoma without Lymph Node Metastasis: Chae A Kim, Hye In Kim, Na Hyun Kim, Tae Yong Kim, Won Bae Kim, Jae Hoon Chung, Min Ji Jeon, Tae Hyuk Kim, Sun Wook Kim, Won Gu Kim; Received October 2, 2024 Accepted January 2, 2025 Published online February 25, 2025; DOI: https://doi.org/10.3803/EnM.2024.2199 [Epub ahead of print]

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Abstract PDF PubReader ePub: Background
We aimed to investigate the prognostic significance of primary tumor size in patients with pT1–T3a N0 M0 papillary thyroid carcinoma (PTC), minimizing the impact of confounding factors.
Methods
A multicenter retrospective study included 5,759 patients with PTC. Those with lymph node metastasis, gross extrathyroidal extension (ETE), and aggressive variants were excluded. Patients were categorized by primary tumor size (≤1, 1.1–2, 2.1–4, and >4 cm) and subdivided based on the presence of microscopic ETE (mETE).
Results
The median age was 48.0 years, and 87.5% were female. The median primary tumor size was 0.7 cm, with mETE identified in 43.7%. The median follow-up was 8.0 years, with an overall recurrent/persistent disease rate of 2.8%. Multivariate analysis identified male sex, larger tumor size, and the presence of mETE as significant prognostic risk factors. The 10-year recurrent/persistent disease rates for tumors ≤1, 1.1–2, 2.1–4, and >4 cm were 2.5%, 4.7%, 11.1%, and 6.0%, respectively. The 2.1–4 cm group had a significantly higher hazard ratio (HR), with the >4 cm group had the highest HR than the ≤1 cm group. Patients with mETE had a higher recurrent/persistent disease rate (4.5%) than those without, with rates by tumor size being 2.6%, 5.6%, 16.7%, and 8.2%.
Conclusion
Larger tumor size and the presence of mETE significantly increased the risk of recurrent/persistent disease in PTC. Patients with pT2–T3a N0 M0 PTC (>2 cm) had a recurrent/persistent disease risk exceeding 5%, warranting vigilant management.

Prevalence of Mortality and Vascular Complications in Older Patients with Diabetes in Korea: Kwang Joon Kim, Jeongmin Lee, Yang Sun Park, Yong-ho Lee, Kyeong Hye Park, Hee-Won Jung, Chang Oh Kim, Man Young Park, Hun-Sung Kim, Bong-Soo Cha; Received September 9, 2024 Accepted January 2, 2025 Published online February 18, 2025; DOI: https://doi.org/10.3803/EnM.2024.2173 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
This study investigated the prevalence of diabetes mellitus (DM) and impaired fasting glucose, as well as their management and comorbidities among older Korean adults.
Methods
Data from 269,447 individuals aged 65 years and older from the Korean National Health Insurance Service between 2000 and 2019 were analyzed to evaluate trends in DM prevalence, healthcare utilization, mortality, and complications.
Results
Among 269,447 individuals, 18.6% (n=50,159/269,447) were diagnosed with DM and 27.0% (n=72,670/269,447) had impaired fasting glucose. The DM group had the highest body mass index, waist circumference, and prevalence of current smokers (P<0.001) but not the highest hypertension prevalence. From 2010 to 2019, the prevalence of DM and impaired fasting glucose increased from 15.5% to 21.9% and from 26.0% to 30.6%, respectively. Cancer-related mortality in DM was 1.15 times higher than in those with normal glucose tolerance (P<0.001), and cardiovascular disease-related mortality was 1.32 times higher (P<0.001); all mortalities were higher in female participants. Myocardial infarction (hazard ratio [HR], 1.34; P<0.001), stroke (HR, 1.24; P<0.001), and heart failure (HR, 1.13; P<0.001) were significantly higher in those with DM.
Conclusion
This is the first study to investigate the prevalence of DM and related complications in older individuals based on longterm representative data in Korea. These results highlight the necessity for targeted interventions to enhance management and outcomes in this population.

Study Protocol of Expanded Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro-EXP): Jae Hoon Moon, Eun Kyung Lee, Wonjae Cha, Young Jun Chai, Sun Wook Cho, June Young Choi, Sung Yong Choi, A Jung Chu, Eun-Jae Chung, Yul Hwangbo, Woo-Jin Jeong, Yuh-Seog Jung, Kyungsik Kim, Min Joo Kim, Su-jin Kim, Woochul Kim, Yoo Hyung Kim, Chang Yoon Lee, Ji Ye Lee, Kyu Eun Lee, Young Ki Lee, Hunjong Lim, Do Joon Park, Sue K. Park, Chang Hwan Ryu, Junsun Ryu, Jungirl Seok, Young Shin Song, Ka Hee Yi, Hyeong Won Yu, Eleanor White, Katerina Mastrocostas, Roderick J. Clifton-Bligh, Anthony Glover, Matti L. Gild, Ji-hoon Kim, Young Joo Park; Received August 9, 2024 Accepted November 29, 2024 Published online February 18, 2025; DOI: https://doi.org/10.3803/EnM.2024.2136 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Active surveillance (AS) has emerged as a viable management strategy for low-risk papillary thyroid microcarcinoma (PTMC), following pioneering trials at Kuma Hospital and the Cancer Institute Hospital in Japan. Numerous prospective cohort studies have since validated AS as a management option for low-risk PTMC, leading to its inclusion in thyroid cancer guidelines across various countries. From 2016 to 2020, the Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro) enrolled 1,177 patients, providing comprehensive data on PTMC progression, sonographic predictors of progression, quality of life, surgical outcomes, and cost-effectiveness when comparing AS to immediate surgery. The second phase of MAeSTro (MAeSTro-EXP) expands AS to low-risk papillary thyroid carcinoma (PTC) tumors larger than 1 cm, driven by the hypothesis that overall risk assessment outweighs absolute tumor size in surgical decision-making.
Methods
This protocol aims to address whether limiting AS to tumors smaller than 1 cm may result in unnecessary surgeries for low-risk PTCs detected during their rapid initial growth phase. By expanding the AS criteria to include tumors up to 1.5 cm, while simultaneously refining and standardizing the criteria for risk assessment and disease progression, we aim to minimize overtreatment and maintain rigorous monitoring to improve patient outcomes.
Conclusion
This study will contribute to optimizing AS guidelines and enhance our understanding of the natural course and appropriate management of low-risk PTCs. Additionally, MAeSTro-EXP involves a multinational collaboration between South Korea and Australia. This cross-country study aims to identify cultural and racial differences in the management of low-risk PTC, thereby enriching the global understanding of AS practices and their applicability across diverse populations.

Brief Report

Association of Steatotic Liver Disease with Retinal Vascular Occlusion: The Influence of Obesity in a Large Health Screening Cohort: Younjin Oh, Su Jeong Song; Received September 21, 2024 Accepted November 17, 2024 Published online February 12, 2025; DOI: https://doi.org/10.3803/EnM.2024.2181 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: In this cross-sectional study, we aimed to investigate the relationship between steatotic liver disease (SLD) and retinal abnormalities in a cohort undergoing health screening. Our study included 353,607 participants who underwent fundus photography and abdominal ultrasonography at least once at the Kangbuk Samsung Health Promotion Center from 2002 to 2022. After adjusting for age and sex, the risk of retinal vein occlusion (RVO) significantly increased with the presence of non-alcoholic fatty liver disease, metabolic dysfunction-associated fatty liver disease, and metabolic dysfunction-associated SLD, with odds ratios of 1.259 (95% confidence interval [CI], 1.050 to 1.510), 1.498 (95% CI, 1.249 to 1.796), and 1.342 (95% CI, 1.121 to 1.605), respectively. However, these associations weakened after adjusting for body mass index. No statistically significant associations were observed with other retinal disorders after adjusting for age, sex, and other confounding factors. Our findings suggest that obesity may mediate the relationship between SLD and RVO, while other retinal abnormalities may be more closely associated with known risk factors rather than SLD itself.

Original Articles

Effects of Sequential Anti-Resorptive Agents on Bone Mineral Density Following Denosumab Withdrawal: A Multicenter Real-World Study in Korea (MAXCARE Study): Jeonghoon Ha, Kyong Yeun Jung, Kyoung Jin Kim, Seong Hee Ahn, Hyo-Jeong Kim, Yoon-Sok Chung, on Behalf of MAXCARE Research Group; Received October 31, 2024 Accepted January 13, 2025 Published online February 11, 2025; DOI: https://doi.org/10.3803/EnM.2024.2227 [Epub ahead of print]

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Abstract PDF PubReader ePub: Background
Denosumab is a potent anti-resorptive agent widely used for osteoporosis. However, its discontinuation results in a ‘rebound phenomenon’ of rapid bone loss, necessitating transition to alternative anti-resorptive therapies. Despite this, there is limited evidence to guide the selection of the most effective agent, particularly among bisphosphonates. This study aimed to evaluate the efficacy of different anti-resorptive therapies following denosumab discontinuation in a real-world clinical setting.
Methods
This retrospective study included 360 patients (low-dose alendronate/calcitriol combination [MXM, n=118], alendronate [ALD, n=53], risedronate [RIS, n=20], ibandronate [IBN, n=30], zoledronic acid [ZOL, n=106], selective estrogen receptor modulator [SERM, n=33]) who received at least 12 months of post-denosumab anti-resorptive therapy. Bone mineral density (BMD) changes from baseline and fracture patterns were assessed over the treatment period.
Results
Baseline characteristics, including age and body mass index, were comparable across groups, with an average of 4.2 denosumab administrations per patient. The SERM group experienced the greatest BMD decline across all sites. Significant BMD reductions in the lumbar spine and femoral neck and in the femoral neck alone were observed in the IBN and RIS groups, respectively. While BMD decline was also observed in the MXM, ALD, and ZOL groups, these changes were not statistically significant.
Conclusion
MXM, ALD, and ZOL mitigated BMD loss following denosumab discontinuation. Conversely, RIS, IBN, and SERM did not adequately prevent BMD decline. These findings underscore the importance of selecting the most appropriate sequential antiresorptive therapy in clinical practice to minimize BMD loss and reduce the risk of adverse outcomes.

Combined PD-1 and CTLA-4 Blockade Increases the Risks of Multiple Pituitary Hormone Deficiency and Isolated Adrenocorticotropic Deficiency: A Prospective Study: Shintaro Iwama, Tomoko Kobayashi, Tetsushi Izuchi, Koji Suzuki, Takanori Murase, Masahiko Ando, Tomoko Handa, Takeshi Onoue, Takashi Miyata, Mariko Sugiyama, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Shoichiro Mori, Tomoyasu Sano, Shusuke Akamatsu, Masashi Akiyama, Makoto Ishii, Hiroshi Arima; Received September 24, 2024 Accepted November 18, 2024 Published online February 11, 2025; DOI: https://doi.org/10.3803/EnM.2024.2180 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) monotherapy induces two types of pituitary immunerelated adverse events (irAEs): multiple pituitary hormone deficiency (Multi-D; impairment of ≥2 anterior pituitary hormones) and isolated adrenocorticotropic hormone (ACTH) deficiency (IAD). Combination therapy with CTLA-4-Ab and anti-programmed cell death-1 antibody (PD-1/CTLA-4-Abs), which is increasingly replacing CTLA-4-Ab monotherapy, frequently causes pituitary irAEs; however, whether it increases Multi-D/IAD incidence is unknown.
Methods
In total, 74 and 748 patients with malignancies treated with PD-1/CTLA-4-Abs and PD-1-Ab, respectively, were prospectively evaluated for ACTH and cortisol levels at baseline and every 6 weeks after treatment initiation, and then observed until the last clinical visit. The characteristics of pituitary irAEs were evaluated by pituitary stimulation tests and compared with those induced by PD-1-Ab monotherapy.
Results
PD-1/CTLA-4-Abs therapy showed higher incidence rates of pituitary irAEs (16/74 [21.6%] vs. 25/748 [3.3%], P<0.001), Multi-D (9/74 [12.2%] vs. 2/748 [0.3%], P<0.001), and IAD (7/74 [9.5%] vs. 23/748 [3.1%], P=0.014) than PD-1-Ab monotherapy. ACTH deficiency was observed in all cases, whereas the prevalence rates of luteinizing hormone deficiency (8/16 [50.0%] vs. 1/25 [4.0%]), follicle-stimulating hormone deficiency (6/16 [37.5%] vs. 1/25 [4.0%]), and thyrotropin deficiency (4/16 [25.0%] vs. 0/25 [0%]) were significantly higher after PD-1/CTLA-4-Abs than after PD-1-Ab treatment. Pituitary enlargement, which was observed only in the Multi-D cases, was significantly more frequent after PD-1/CTLA-4-Abs than after PD-1-Ab treatment (6/16 [37.5%] vs. 0/25 [0%], P=0.002).
Conclusion
This prospective study revealed high risks of both Multi-D and IAD under PD-1/CTLA-4-Abs treatment, emphasizing the need for careful evaluation of pituitary function.

Sex-Specific Cardiovascular Risks and Mortality in Patients with Panhypopituitarism: A Nationwide Cohort Study: Seung Shin Park, Hyunmook Jeong, Chang Ho Ahn, Min Jeong Park, Yong Hwy Kim, Kwangsoo Kim, Jung Hee Kim; Received September 12, 2024 Accepted December 16, 2024 Published online February 11, 2025; DOI: https://doi.org/10.3803/EnM.2024.2176 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Panhypopituitarism is a condition of combined deficiency of multiple pituitary hormones, which requires lifelong hormone replacement therapy. Hormone deficiency or inadequate hormone replacement may contribute to cardiovascular disease. Here, we aimed to investigate the burden of cardiovascular, cerebrovascular diseases and mortality in patients with panhypopituitarism.
Methods
A total of 5,714 patients with panhypopituitarism were enrolled in the Korean National Health Insurance Service database from 2003 to 2020. Panhypopituitarism was defined according to the International Classification of Diseases, 10th Revision (ICD- 10) codes for hypopituitarism, pituitary adenoma, or craniopharyngioma and the continuous prescription of thyroid hormone and glucocorticoids. The risks of all-cause mortality, coronary artery disease (CAD), heart failure (HF), ischemic stroke, and intracranial hemorrhage were compared between patients with panhypopituitarism and age-, sex-, and index year-matched controls.
Results
The mean age of patients with panhypopituitarism and matched controls was 55.1 years, and men accounted for 51.5%. Patients with panhypopituitarism showed significantly higher all-cause mortality compared to matched controls after adjustment for covariates (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.95 to 2.43 in men and HR, 3.09; 95% CI, 2.78 to 3.44 in women). Additionally, there were higher risks of CAD, HF, ischemic stroke, and intracranial hemorrhage in both sexes, except for CAD in men.
Conclusion
Patients with panhypopituitarism have elevated risks of cardiovascular and cerebrovascular diseases as well as increased mortality. These risks are particularly prominent for all-cause mortality in women. Therefore, proactive monitoring for cardiovascular and cerebrovascular complications is required in patients with panhypopituitarism.

Comparison of the Effectiveness and Hypocalcemia Risk of Antiresorptive Agents in Patients with Hypercalcemia of Malignancy: Sung Hye Kong, Seung Shin Park, Jung Hee Kim, Sang Wan Kim, Se Hyun Kim, Jee Hyun Kim, Chan Soo Shin; Received August 2, 2024 Accepted October 29, 2024 Published online February 4, 2025; DOI: https://doi.org/10.3803/EnM.2024.2132 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Hypercalcemia of malignancy (HCM), a major metabolic complication of cancer, is often managed with bisphosphonates (BP) and, increasingly, with denosumab. We aimed to compare the effectiveness and safety of denosumab with that of BP, with or without calcitonin, in treating HCM.
Methods
This retrospective cohort study was conducted at a tertiary hospital from 2017 to 2022 and included 317 patients treated for HCM. Participants were divided into three treatment groups: denosumab, intravenous (IV) BP only, and IV BP combined with calcitonin. The primary outcomes measured were changes in calcium levels and the incidence of hypocalcemia. Analysis of covariance was used to adjust for age, sex, body mass index, creatinine level, type of malignancy, and the use of furosemide and steroids.
Results
The mean participant age was 65 years, and 37.5% were female. After adjustment, both denosumab and IV BPs were found to effectively lower calcium levels. Denosumab led to a decrease of 2.0 mg/dL (−15.9%), while IV BP alone resulted in a reduction of 1.8 mg/dL (−13.9%). The largest reduction, of 2.7 mg/dL (−20.9%), occurred with IV BP and calcitonin. Both denosumab and IV BP+calcitonin yielded their lowest calcium levels within 48 hours, whereas the IV BP only group reached a nadir within 72 hours. Despite these differences in treatment effectiveness, hypocalcemia occurred significantly less frequently in the denosumab group compared to the other groups.
Conclusion
Denosumab and IV BP were similarly effective in reducing calcium levels. However, IV BP combined with calcitonin yielded a more rapid and pronounced decrease.

Time to Insulin Therapy and Severe Hypoglycemia in Korean Adults Initially Diagnosed with Type 2 Diabetes: A Nationwide Study: You-Bin Lee, Kyungdo Han, Bongsung Kim, So Hee Park, Kyu Yeon Hur, Gyuri Kim, Jae Hyeon Kim, Sang-Man Jin; Received July 4, 2024 Accepted November 19, 2024 Published online February 4, 2025; DOI: https://doi.org/10.3803/EnM.2024.2082 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
We examined the distribution of time to insulin therapy (TIT) post-diabetes diagnosis and the hazard of severe hypoglycemia (SH) according to TIT in Korean adults initially diagnosed with type 2 diabetes (T2D) and who progressed to insulin therapy.
Methods
Using data from the Korean National Health Insurance Service (2002 to 2018), we selected adult incident insulin users (initially diagnosed as T2D) who underwent health examinations between 2009 and 2012. The hazards of SH, recurrent SH, and problematic hypoglycemia were analyzed according to groups categorized using the TIT and clinical risk factors for SH (TIT ≥5 years with risk factors, TIT ≥5 years without risk factors, 3 ≤TIT <5 years, 1 ≤TIT <3 years, and TIT <1 year).
Results
Among 41,637 individuals, 14,840 (35.64%) and 10,587 (25.43%) initiated insulin therapy within <5 and <3 years postdiabetes diagnosis, respectively. During a median 6.53 years, 3,406 SH events occurred. Compared to individuals with TIT ≥5 years and no risk factor for SH, individuals with TIT <3 years had higher outcome hazards in a graded manner (adjusted hazard ratio [95% confidence intervals] for any SH: 1.117 [0.967 to 1.290] in those with 3 ≤TIT <5 years; 1.459 [1.284 to 1.657] in those with 1 ≤ TIT <3 years; and 1.515 [1.309 to 1.754] in those with TIT <1 year). This relationship was more pronounced in the non-obese subpopulation.
Conclusion
Among adults who progressed to insulin therapy after being diagnosed with T2D, a shorter TIT was not uncommon and may predict an increased risk of SH, particularly in non-obese patients.

Prognostic Indicators and Comparative Treatment Outcomes in High-Risk Thyroid Cancer with Laryngotracheal Invasion: Eman A. Toraih, Jessan A. Jishu, Mohammad H. Hussein, Aly A. M. Shaalan, Manal S. Fawzy, Emad Kandil; Received May 9, 2024 Accepted October 18, 2024 Published online January 22, 2025; DOI: https://doi.org/10.3803/EnM.2024.2033 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Laryngotracheal invasion occurs in a subset of patients with well-differentiated thyroid cancer (WDTC) and is associated with a poor prognosis. We aimed to analyze patterns and predictors/outcomes related to this high-risk manifestation.
Methods
This population-based analysis utilized the Surveillance, Epidemiology, and End Results (SEER) registry (2000 to 2015) to identify WDTC patients. Temporal trends and geographic variation in invasion rates were assessed. Logistic regression and propensity score matching were employed to identify predictors of secondary malignancy, mortality, and treatment impact on overall and thyroid cancer (TC)-specific survival.
Results
Of 131,721 WDTC patients, 1,662 (1.3%) had tracheal invasion and 976 (0.7%) had laryngeal invasion at diagnosis. Tracheal and laryngeal invasion rates declined from 3.7%–0.7% and 1.5%–0.6%, respectively, from 2000 to 2015. Compared to 98,835 noninvasive cases, patients with laryngotracheal invasion were older and more often male, Asian, and Hispanic (all P<0.001). This group had larger tumors with higher rates of nodal (N1: 61.8% vs. 15.1%) and distant metastases (M1: 9.3% vs. 0.4%). Age ≥55 years (hazard ratio [HR], 1.19; P=0.004) and metastases (HR, 1.75; P<0.001) increased TC-specific mortality, whereas the converse pattern was found for Asian race (HR, 0.63; P=0.002) and surgery (HR, 0.35; P<0.001). In rigorously matched groups to control confounding, adding radioactive iodine to surgery reduced mortality by 30% (P<0.001). However, external beam radiation and systemic therapy did not improve survival over surgery alone.
Conclusion
Laryngotracheal invasion is present in 0.7% to 1.3% of cases, conferring over double the mortality risk. Radioactive iodine with surgery improves outcomes in this aggressive WDTC subset.

Risk of Osteoporotic Fractures among Patients with Thyroid Cancer: A Nationwide Population-Based Cohort Study: Eu Jeong Ku, Won Sang Yoo, Yu Been Hwang, Subin Jang, Jooyoung Lee, Shinje Moon, Eun Kyung Lee, Hwa Young Ahn; Received July 13, 2024 Accepted November 11, 2024 Published online January 15, 2025; DOI: https://doi.org/10.3803/EnM.2024.2101 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
The associations between thyroid cancer and skeletal outcomes have not been thoroughly investigated. We aimed to investigate the risk of osteoporotic fractures in patients with thyroid cancer compared to that in a matched control group.
Methods
This retrospective cohort study included 2,514 patients with thyroid cancer and 75,420 matched controls from the Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC, 2006–2019). The rates of osteoporotic fractures were analyzed, and associations with the levothyroxine dose were evaluated.
Results
Patients with thyroid cancer had a significantly lower risk of fracture than did the control group (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.69 to 0.94; P=0.006). Patients diagnosed with thyroid cancer after the age of 50 years (older cancer group) had a significantly lower risk of fracture than did those in the control group (HR, 0.72; 95% CI, 0.6 to 0.85; P<0.001), especially those diagnosed with spinal fractures (HR, 0.66; 95% CI, 0.51 to 0.85; P=0.001). Patients in the older cancer group started osteoporosis treatment earlier than did those in the control group (65.5±7.5 years vs. 67.3±7.6 years, P<0.001). Additionally, a lower dose of levothyroxine was associated with a reduced risk of fractures.
Conclusion
In the clinical setting, the risk of fracture in women diagnosed with thyroid cancer after the age of 50 years was lower than that in the control group, which was caused by more proactive osteoporosis treatment in postmenopausal women with thyroid cancer.

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