Journal of Clinical Endocrinology & Metabolism最新文献

Context: The use of corticosteroids (CS) has been associated with higher body mass index (BMI) and waist circumference (WC) in cross-sectional studies. However, longitudinal data are scarce, particularly for locally administered forms.

Design: We analyzed weight and waist circumference changes in 81 361 Lifelines Cohort Study participants (mean age 46.3 years, mean BMI 26.0 kg/m2, 41% male, mean follow-up 3.9 years) via linear regression. Sensitivity analyses included stratification by sex and BMI. Short-term weight changes post-start were assessed in a subset using linear mixed-effect models.

Results: We found 23.8% CS users during the study period. Individuals reporting any new use of CS gained significantly more weight compared to nonusers at follow-up (β .034 kg/year, P = .021), particularly among those initiating local CS use (β .037 kg/year, P = .017). Use of new systemic CS was associated with increased WC (β .200 cm/year, P < .001). Discontinuation of CS led to decreased WC (β -.078 cm/year, P = .028). These effects were particularly observed in female participants and individuals with BMI ≥25 kg/m2, but not in male participants and those with BMI < 25 kg/m2. Short-term weight-inducing effects of CS were not observed in the weeks after initiation of CS use.

Conclusion: This study demonstrates that CS use, including locally administered forms, is associated with long-term increases in weight and WC, notably in female individuals and those with overweight or obesity. Discontinuing CS was linked to reductions in WC. These findings underscore the need to carefully assess chronic systemic and local CS use, as discontinuation could benefit obesity-related outcomes in certain patients.

Context: Immune checkpoint inhibitor (ICI)-related hypothyroidism is mostly irreversible and prompt thyroid hormone replacement therapy is crucial, especially for patients undergoing neoadjuvant immunotherapy.

Objective: This study aimed to propose a novel titration strategy for ICI-related hypothyroidism, evaluate levothyroxine (LT4) dose differences between hypothyroidism patterns, and develop a predictive equation for the optimal LT4 dose.

Design: Retrospective study.

Setting: Tertiary academic hospital.

Patients: A total of 109 patients with ICI-related hypothyroidism.

Interventions: Rapid vs conventional titration strategy.

Main outcome measures: The time to achieve normal free thyroxine and TSH levels.

Results: Patients with transient thyrotoxicosis followed by overt hypothyroidism required higher LT4 doses to achieve a euthyroid state compared to isolated overt hypothyroidism, with a mean difference of 0.23 μg/kg/day (95% CI, 0.08-0.38). In patients with ICI-related overt hypothyroidism and no cardiac disease, who had elevated TSH levels within 4 weeks of the last documented low or normal TSH, a rapid titration strategy was implemented. This strategy significantly improved the cumulative incidence of achieving normal free thyroxine and TSH levels compared to conventional titration strategy (hazard ratio, 4.44; 95% CI, 2.24-8.82; and hazard ratio, 4.11; 95% CI, 2.18-7.73, respectively), with a comparable safety profile. Predicted LT4 dose at euthyroid state (µg/kg/day) = (-0.016 × body weight) + (0.109 × baseline TSH level) + 2.661 for patients with thyrotoxicosis followed by overt hypothyroidism.

Conclusion: LT4 requirements vary depending on the subtype of ICI-related hypothyroidism. The rapid titration strategy reduced the time to achieve a euthyroid state without a significant increase in adverse effects compared to conventional LT4 replacement therapy.

Objective: Type 2 diabetes risk prediction models lack the option to predict risk conditional on initiating different preventive interventions. Our objective was to develop and validate a diabetes risk prediction model with individualized preventive intervention effects among racially diverse populations.

Methods: The derivation cohort included participants in the Diabetes Prevention Program (DPP) trial randomized to placebo, metformin, or intensive lifestyle intervention (n = 2640). A risk prediction model for incident diabetes was developed using Cox proportional hazards regression using clinically available predictors: sex, glycated hemoglobin, fasting plasma glucose (FPG), body mass index (BMI), triglycerides, and intervention. To create individualized intervention effects, pairwise interactions between intervention and age, FPG, and BMI were included. The discrimination, calibration, and net benefit of the model's 3-year predictions for incident diabetes were internally validated within the DPP and externally validated among participants with prediabetes in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 2104).

Results: In DPP and MESA, mean (SD) age was 51 years (11) and 64 (10), and 67% and 50% of participants were women, respectively. The mean C-statistic was 0.71 [95% confidence interval (CI): 0.68, 0.74] in DPP and 0.86 (95% CI: 0.83, 0.88) in MESA. The optimal preventive intervention (lowest 3-year risk) was lifestyle for 86% and 97% of DPP and MESA participants, respectively, and metformin for the remaining. Model performance was similar across race/ethnicity groups.

Conclusion: This is the first study to develop and validate a diabetes risk prediction model with individualized preventive intervention effects that may improve clinical decision-making and diabetes prevention.

Context: Epidemiological data suggest that participants with lower vs higher body mass index (BMI) resist exposure to the obesogenic environment.

Objective: To test this, we analyzed the relationship between overfeeding-induced weight and fat mass gains with baseline BMI and body fat percentage.

Methods: In this controlled intervention study, 34 men (age 26 ± 5 years; BMI 25.5 ± 2.4 kg/m2; body fat [by dual-energy x-ray absorptiometry] 19.3 ± 5.1%) consumed for 8 weeks 40% more energy than needed at weight maintenance. The energy costs of weight and fat mass gain were calculated as the 8-week excess energy consumed divided by weight or fat mass gain. Energy expenditure (baseline and after overfeeding) was determined using a metabolic chamber and doubly labeled water. Transcriptomic analysis was conducted from abdominal subcutaneous adipose tissue samples.

Results: Body weight increased 7.2 ± 2.1 kg and fat mass 4.0 ± 1.4 kg. There was no statistical association between baseline BMI and weight and fat mass gains. However, baseline body fat percentage was significantly associated with weight (r = 0.57) and fat mass (r = 0.59) gains. Body fat percentage was also statistically associated with energy cost of weight (r = -0.38) and fat mass (r = -0.40) gains. Metabolic adaptation in energy expenditure (adaptive thermogenesis) was unrelated to the energy cost of weight and fat mass gains. Transcriptomics analysis showed that high energy cost of weight gain was associated with upregulation of inflammation-related pathways.

Conclusion: Body fat percentage at baseline was inversely associated with overfeeding-induced weight and fat gain resistance. The underlying compensatory response appears unrelated to changes in energy expenditure.

Context: The glucose management indicator (GMI) is an estimated glycated hemoglobin (A1C) derived from sensor glucose. Though it is being used to approximate A1C in clinical trials, there are no data on direction and magnitude of change in GMI vs A1C after an intervention.

Objective: To evaluate the magnitude and direction of changes in A1C compared to GMI across different baseline glycemic categories in type 1 diabetes (T1D) clinical trials.

Methods: Baseline and 3-month central laboratory-measured A1C and estimated GMI from sensor glucose were collected from T1D clinical trials (DCLP3, DCLP5, and WISDM), encompassing children, adolescents, adults, and older adults. Magnitude and direction of changes (baseline-3 months) in A1C vs GMI were compared overall across the studies and by stratified baseline A1C (<7%, 7%-9%, >9%).

Results: A modest correlation was found between changes in A1C and GMI (r = 0.34). Participants with baseline A1C > 9% had larger reductions in A1C compared to GMI (-1.2 [-2.1 to -0.6] vs -0.6 [-0.94 to 0], P < .01). Those with baseline A1C between 7% and 9% showed a greater decline in A1C than GMI (-0.4 [-0.9 to -0.1] vs -0.12 [-0.49 to 0.21], P < .01). No significant difference was observed for baseline A1C < 7%.

Conclusion: Change in GMI is influenced by the baseline A1C of the participants and it underestimates the true change in A1C. Use of GMI as an endpoint in clinical trials may not reliably capture efficacy of an intervention in T1D trials or real-world studies.

Context: Very-low-calorie ketogenic diet (VLCKD) is used for weight loss and management of obesity-related comorbidities.

Objective: We aimed at evaluating the effects of VLCKD on body composition and energy metabolism.

Methods: This prospective outpatient study included 17 women with obesity (mean age 41.6 years; body mass index 37.5 kg/m2) who followed a 1-month VLCKD (700-800 kcal/day, carbohydrate 11%, fat 46%, protein 43%) at the University Hospital of Pisa. Measurements of 24-hour energy expenditure (24hEE) and substrate oxidation were conducted in a metabolic chamber at day 1 (V1), day 8 (V2), and day 29 (V3). Body composition was assessed by Dual energy X-ray absorptiometry. Twenty-two women with obesity fed a balanced isocaloric diet served as controls.

Results: Compared with controls, carbohydrate oxidation (CarbOx) was lower, whereas fat oxidation (FatOx) and protein oxidation (ProtOx) were higher in the VLCKD group at V1. CarbOx decreased by 65%, while FatOx increased by 11% at V3. The rate of ProtOx was already higher than in controls at V1 and remained stable throughout the study. After 1 month, body weight decreased by 7%, reflecting an 8.8% reduction in fat mass and a 5.6% reduction in lean soft tissue (LST). A 10% decrease in 24hEE and 24-hour sleeping metabolic rate was observed at V3 compared with V1.

Conclusion: VLCKD promotes weight loss in women with obesity. Our findings highlight the shift in energy metabolism towards increased FatOx accompanied by a modest increase in protein oxidation, a decrease in LST and a reduction in EE.

Context: Congenital hypogonadotropic hypogonadism (CHH) in infant boys is a rare disorder that can manifest as micropenis and/or cryptorchidism. Mini-puberty is considered a window of opportunity for CHH diagnosis and treatment. The lack of testosterone (T) elevation during this period is the gold standard for CHH diagnosis, but hormonal evaluation is not always available at this time.

Objectives: The aim was to compare inhibin B (INHB), anti-Müllerian hormone (AMH), T, LH, and FSH between infant boys (1 to 365 days) with micropenis and/or cryptorchidism due to isolated CHH (iCHH), CHH as part of combined pituitary hormone deficiency (CPHD), or of idiopathic origin (controls) and to determine discriminating cutoffs for CHH diagnosis based on sensitivity (Se) and specificity (Sp).

Methods: This multicenter study from 7 University Hospitals in France included 138 boys aged 0 to 12 months (58 with iCHH, including 28 with a positive molecular diagnosis, 32 with CPHD, and 48 controls). Four periods of interest were studied: between 1 to 4 days, 15 to 65 days (early mini-puberty, corresponding to the T peak), 66 to 179 days (late mini-puberty), and 180 to 365 days (post mini-puberty).

Results: Out of mini-puberty, the best-discriminating hormones were INHB between 1 to 4 days (Se/Sp 100%/75% at 150 pg/mL and 89%/100% at 85 pg/mL) and INHB and AMH after 180 days (INHB: Se/Sp 100%/100% at 100 pg/mL; AMH: Se/Sp 100%/92% at 600 pmol/L, and 75%/100% at 370 pmol/L). INHB and/or AMH discriminating performances were good (area under the receiver operating characteristic curve ≥ 0.95) across all 4 periods.

Conclusion: Inhibin B and/or AMH can be used to diagnose CHH in boys < 1 year of age.

Context: The relationship between initial changes in estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR), and their independent association with clinical outcomes in type 2 diabetes (T2D) patients receiving sodium-glucose cotransporter 2 inhibitors (SGLT2is), remains unclear.

Objective: This study aimed to investigate the association between initial changes in eGFR and UACR with consequent cardiovascular and kidney outcomes in an Asian population with T2D following SGLT2i treatment in a real-world setting.

Methods: Using a large multicenter medical database in Taiwan, we analyzed 8222 T2D patients with baseline and 3-month follow-up eGFR and UACR measurements, receiving SGLT2is between June 1, 2016, and December 31, 2021. We assessed risks of major adverse renal events (MARE), major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF), and all-cause mortality using a Cox proportional hazards model.

Results: After 3 months of SGLT2i treatment, patients were categorized based on early changes in eGFR (no decline, 0%-10% decline, > 10% decline) and UACR (no reduction, 0%-30% reduction, > 30% reduction). Among those with no initial eGFR decline (40.9%), 19.8% had no initial UACR reduction, 8.4% had 0% to 30% reduction, and 12.7% had greater than 30% reduction. For those with greater than 10% initial eGFR decline (21.5%), 6.5% had no UACR reduction, 4.3% had 0% to 30% reduction, and 10.7% had greater than 30% reduction. Patients with greater than 10% initial eGFR decline but no UACR reduction showed higher risks of MARE (adjusted HR [aHR]: 2.34; 95% CI, 1.32-4.15), MACE (aHR: 1.83; 95% CI, 1.01-3.29), and HHF/cardiovascular death (aHR: 1.93; 95% CI, 1.05-3.55) compared to those with modest early eGFR decline and UACR reduction.

Conclusion: T2D patients experiencing profound early eGFR decline without concordant UACR reduction while on SGLT2is represent a high-risk subgroup with worse clinical outcomes. These findings suggest the need for closer monitoring and potentially more aggressive therapeutic strategies for this patient population.