Daily Endocrinology Research Analysis
Three high-impact endocrinology papers stand out today: a nationwide stepped-wedge cluster randomized trial shows fracture liaison services reduce both subsequent fragility fractures and mortality; a large Japanese real-world cohort finds SGLT2 inhibitors halve the risk of initiating insulin versus DPP-4 inhibitors; and a nationwide Korean cohort quantifies high antithyroid drug failure in Graves' disease, supporting broader consideration of definitive therapy. Together, these studies inform ser
Summary
Three high-impact endocrinology papers stand out today: a nationwide stepped-wedge cluster randomized trial shows fracture liaison services reduce both subsequent fragility fractures and mortality; a large Japanese real-world cohort finds SGLT2 inhibitors halve the risk of initiating insulin versus DPP-4 inhibitors; and a nationwide Korean cohort quantifies high antithyroid drug failure in Graves' disease, supporting broader consideration of definitive therapy. Together, these studies inform service design, therapeutic sequencing, and hyperthyroidism management.
Research Themes
- Fracture prevention and secondary prevention services
- Therapeutic sequencing in type 2 diabetes (insulin-sparing strategies)
- Outcomes of treatment strategies in Graves' disease
Selected Articles
1. Fracture liaison service (FLS) is associated with lower subsequent fragility fracture risk and mortality: NoFRACT (the Norwegian capture the fracture initiative).
In a nationwide, register-supported stepped-wedge cluster randomized trial including 100,198 fracture patients, implementation of an FLS program reduced subsequent fragility fractures (HR 0.87 in women; 0.90 in men) and all-cause mortality (HR 0.82 in women; 0.85 in men) over up to 4.7 years. These findings support FLS as an effective secondary prevention strategy.
Impact: Demonstrates real-world effectiveness of a scalable service model that lowers both fracture recurrence and mortality at population scale. Provides high-grade evidence to guide health system adoption of FLS.
Clinical Implications: Health systems should implement standardized FLS pathways for patients ≥50 years after low-energy fractures to reduce secondary fractures and mortality, integrating osteoporosis assessment and treatment with registry tracking.
Key Findings
- FLS reduced subsequent fragility fracture risk by 13% in women (HR 0.87, 95% CI 0.83–0.92) and 10% in men (HR 0.90, 95% CI 0.81–0.99).
- FLS reduced all-cause mortality by 18% in women (HR 0.82, 95% CI 0.79–0.86) and 15% in men (HR 0.85, 95% CI 0.81–0.89).
- Stepped-wedge cluster implementation across three clusters over 2015–2018 enabled pragmatic evaluation within routine care using national registry data.
Methodological Strengths
- Stepped-wedge cluster-randomized pragmatic design with national registry linkage
- Very large sample size (N=100,198) with sex-stratified hazard ratios and CIs
Limitations
- Potential residual confounding and misclassification inherent to registry data
- Stepped-wedge design susceptible to temporal trends despite adjustment
Future Directions: Assess cost-effectiveness, implementation fidelity, and equity of FLS at scale; evaluate optimization of pharmacotherapy (e.g., denosumab vs bisphosphonates) within FLS pathways.
UNLABELLED: Subsequent fracture rates and associated mortality were compared before and after the introduction of fracture liaison service (FLS). In 100,198 women and men, FLS was associated with 13% and 10% lower risk of subsequent fragility fractures and 18% and 15% lower mortality. The study suggests that FLS may prevent fractures. PURPOSE: Efficient fracture prevention strategies are warranted to control the global fracture burden. We investigated the effect of a standardized fracture liaison service (FLS) intervention on subsequent fracture risk and mortality. METHODS: The NoFRACT study was designed as a multicenter, pragmatic, register-supported, stepped-wedge cluster-randomized trial. The FLS intervention was introduced in three clusters with 4-month intervals starting May 2015 through December 2018 and included evaluation of osteoporosis and treatment in patients over 50 years with a low-energy fracture. Based on data from the Norwegian Patient Registry, patients with index fractures were assigned to the control period (2011-2015) or intervention period (2015-2018) depending on the time of fracture. Rates of subsequent fragility fractures (distal forearm, proximal humerus, or hip) and all-cause mortality were calculated. RESULTS: A total of 100,198 patients (mean age 69.6 years) suffered an index fracture of any type. During a maximum follow-up of 4.7 years, 11% (6948) of the women and 6% (2014) of the men experienced a subsequent fragility fracture, and 20% (14,324) of the women and 22% (8,326) of the men died. FLS was associated with 13% lower subsequent fragility fracture risk in women (hazard ratio (HR) 0.87, 95% confidence intervals (CI) 0.83-0.92) and 10% in men (HR 0.90, 95% CI 0.81-0.99) and 18% lower mortality in women (HR 0.82, 95% CI 0.79-0.86) and 15% in men (HR 0.85, 95% CI 0.81-0.89). CONCLUSION: A standardized FLS intervention was associated with a lower risk of subsequent fragility fractures and mortality and may contribute to reduce the global fracture burden.
2. Risk of insulin initiation with sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: A real-world claims database study in Japan.
In a propensity score–matched national claims cohort (n=36,976), initiating SGLT2 inhibitors versus DPP-4 inhibitors was associated with a 54% lower hazard of insulin initiation and reduced need for add-on oral antidiabetic and antihypertensive medications. These findings support early SGLT2i use to delay insulin therapy in T2DM.
Impact: Provides high-quality real-world comparative effectiveness data on insulin-sparing with SGLT2i versus DPP-4i, informing first-line or early add-on choices where insulin initiation is a key outcome.
Clinical Implications: Prefer SGLT2 inhibitors over DPP-4 inhibitors when aiming to delay insulin initiation and reduce treatment intensification, while also considering cardiorenal benefits and patient profiles.
Key Findings
- Insulin initiation risk was significantly lower with SGLT2i vs DPP-4i (HR 0.46, 95% CI 0.28–0.74; IR 0.95 vs 2.12 per 1000 person-years).
- Add-on oral antidiabetic medication risk was lower with SGLT2i (HR 0.66, 95% CI 0.64–0.69).
- Add-on antihypertensive medication risk was modestly lower with SGLT2i (HR 0.90, 95% CI 0.85–0.95).
Methodological Strengths
- Large nationwide claims database with propensity score 1:1 matching
- Time-to-event analysis with Cox models and multiple intensification outcomes
Limitations
- Observational design with potential residual confounding and coding misclassification
- Follow-up duration heterogeneity inherent to claims data
Future Directions: Replicate in other healthcare systems; assess subgroup effects (e.g., baseline A1c, CKD, CVD) and mechanisms underlying reduced intensification; evaluate cost-effectiveness.
AIMS: Insulin therapy is a cornerstone in type 2 diabetes mellitus (T2DM) management, but its use is associated with several barriers, including hypoglycaemia, fear of injections and high costs. We compared the risk of insulin initiation and other treatment intensification between patients with T2DM newly treated with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) versus those newly treated with a dipeptidyl peptidase-4 inhibitor (DPP4i). MATERIALS AND METHODS: This Japanese retrospective cohort study was conducted between 1 January 2015 and 31 March 2023 using the JMDC Claims Database. Patients with T2DM newly treated with an SGLT2i or a DPP4i were matched 1:1 using propensity score (n = 18 488 each). Incidence rates (IR) of insulin initiation, other antidiabetic drugs (OAD) and antihypertensive drugs added onto baseline treatment were calculated for each treatment group. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using a Cox proportional hazards model. RESULTS: The IR of insulin initiation was 0.95 and 2.12 per 1000 person-years in the SGLT2i and DPP4i groups, respectively, with significantly lower risk in the SGLT2i group than in the DPP4i group (HR 0.46, 95% CI: 0.28-0.74, p = 0.001). The risks of OAD (HR 0.66, 95% CI: 0.64-0.69, p < 0.001) and antihypertensive drugs (HR 0.90, 95% CI: 0.85-0.95, p < 0.001) added onto baseline treatment were lower in the SGLT2i group than in the DPP4i group. CONCLUSIONS: The risk of insulin initiation was lower in patients with T2DM newly treated with an SGLT2i than in those newly treated with a DPP4i. SGLT2i may reduce or delay the need for insulin therapy.
3. Unveiling Risk Factors for Treatment Failure in Patients with Graves' Disease: A Nationwide Cohort Study in Korea.
Among 452,001 Korean patients with Graves’ disease followed a median 8.5 years, treatment failure occurred in 58.5% with antithyroid drugs versus 21.3% with radioiodine and 2.1% with thyroidectomy. ATD failure hazard was 2.81 times that of RAI; higher RAI doses (≥10 mCi) reduced failure by 37%.
Impact: Defines real-world failure rates across major Graves’ disease treatments at national scale, highlighting the limitations of prolonged ATD therapy and dose–response benefits of radioiodine.
Clinical Implications: Consider earlier definitive therapy (adequate-dose radioiodine or surgery) in patients at high risk of ATD failure; if selecting RAI, doses ≥10 mCi may improve success.
Key Findings
- Treatment failure rates: ATD 58.5%, RAI 21.3%, thyroidectomy 2.1% over median 8.5 years.
- ATD had a 2.81-fold higher hazard of treatment failure compared with RAI.
- Radioiodine ≥10 mCi reduced failure by 37% versus <10 mCi.
Methodological Strengths
- Very large nationwide cohort (n=452,001) with long median follow-up
- Clear operational definition of treatment failure and dose–response analysis for RAI
Limitations
- Observational design with potential confounding by indication and unmeasured factors
- Administrative data may lack detailed clinical variables (e.g., TRAb levels, goiter size)
Future Directions: Identify predictors of ATD failure to personalize initial therapy; evaluate patient-centered outcomes and quality of life across modalities; assess barriers to definitive therapy uptake.
BACKGRUOUND: Antithyroid drug (ATD) treatment is the preferred initial treatment for Graves' disease (GD) in South Korea, despite higher treatment failure rates than radioactive iodine (RAI) therapy or thyroidectomy. This study aimed to evaluate the incidence of treatment failure associated with the primary modalities for GD treatment in real-world practice. METHODS: We included 452,001 patients diagnosed with GD between 2004 and 2020 from the Korean National Health Insurance Service-National Health Information Database. Treatment failure was defined as switching from ATD, RAI, or thyroidectomy treatments, and for ATD specifically, inability to discontinue medication for over 2 years. RESULTS: Mean age was 46.2 years, with females constituting 70.8%. Initial treatments for GD included ATDs (98.0%), thyroidectomy (1.3%), and RAI (0.7%), with a noted increment in ATD application from 96.2% in 2004 to 98.8% in 2020. During a median follow- up of 8.5 years, the treatment failure rates were 58.5% for ATDs, 21.3% for RAI, and 2.1% for thyroidectomy. Multivariate analysis indicated that the hazard ratio for treatment failure with ATD was 2.81 times higher than RAI. RAI treatments ≥10 mCi had 37% lower failure rates than doses <10 mCi. CONCLUSION: ATDs are the most commonly used for GD in South Korea, followed by thyroidectomy and RAI. Although the risk of treatment failure for ATD is higher than that of RAI therapy, initial RAI treatment in South Korea is relatively limited compared to that in Western countries. Further studies are required to evaluate the cause of low initial RAI treatment rates in South Korea.