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Background: Understanding pharmacokinetics (PK) and pharmacodynamics (PD) of the sustained-release liothyronine (SR-T3) is of paramount importance to design therapeutic regimens that are able to simulate normal thyroid hormone secretion while avoiding excursions in the T3 serum concentration. Here, we designed a parallel randomized clinical trial to characterize the PK and PD of the combined preparations of LT4 + SR-T3 in hypothyroid patients. Methods: Radioiodine-treated hypothyroid patients over 20 years of age, who attained euthyroidism with LT4 monotherapy were recruited from the Endocrine Clinic in Tehran. The patients were allocated to two intervention groups of group A: 9 µg SR-T3 plus 68.5 μg LT4 (ratio 1:7.5) and group B: 12 µg SR-T3 plus 60 µg LT4 (ratio 1:5), and a control group with LT4 monotherapy. For PD study, thyroid hormone profile was evaluated at 8 and 12 weeks intervals after intervention. To assess PK properties of SR-T3, T3-Cmax, T3-Tmax and AUC0 − 24 were calculated at the last visit. Results: Serum T4 and FT4 concentrations decreased in the intervention groups after 3 months. No significant difference was observed in serum T3 and FT3 concentrations before and after intervention. Serum T3/T4 ratio increased significantly in the intervention groups after intervention, with the highest increase in group B from 8.6 ± 2.03 at baseline to 12.2 ± 1.6. Comparison of trial groups at follow-up showed no differences in serum TSH, T4, T3 and T3/T4 concentrations among different groups. During 24 h, minimal variation in serum T3 concentration was observed in group B with mean ∆T3 of 15.4 ± 10.5 ng/dl. T3-Tmax, T3-Cmax and AUC0 − 24 in the combined sustained-release preparation were 4.38 ± 1.1 h., 101.0 ± 5.7 ng/dl and 2257 ± 110 ng.h/L, respectively which were significantly different from the control group. Conclusion: Combined treatment with a single dose of SR-T3 plus LT4 is associated with increased serum T3/T4 ratio and minimal excursions in serum T3 concentration during 24 h; however, it was not significantly different from the control group. To incorporate sustained-release T3 in the management of hypothyroidism, a higher ratio of SR-T3 to LT4 than that of the previously recommended by the international organizations is suggested. IRCT registration number: IRCT20100922004794N13. https://www.irct.ir/search/result?query=IRCT20100922004794N13. Registration date: 08/12/2021. [ABSTRACT FROM AUTHOR]

Objective: Obesity and metabolic syndrome, which has an increasing prevalence among adolescence, are associated with metabolic abnormalities. This study investigates the role of adolescent obesity phenotypes in predicting the incidence of early adulthood type 2 diabetes mellitus (T2DM). Research Design and Methods: Participants were divided into four obesity phenotypes: Metabolically healthy normal weight (MHNW), metabolically healthy obese (MHO), metabolically unhealthy normal weight (MUNW), and metabolically unhealthy obese (MUO). Multivariate‐adjusted hazard ratios (HRs) were calculated for T2DM incidence. Results: In this cohort study, 2306 Tehranian adolescents with an average age of 15.1 ± 2.4 years were included. The median (IQ 25–75) follow‐up was 15.5 (12.8–17.1) years and the median (IQ 25–75) age of participants at the end of follow‐up was 30 (26–32) years old. The incidence rate of T2DM during the early adulthood was [1.37 (95% CI: 0.89–2.10)] and [3.18 (95% CI: 2.44–4.16)] per 1000 person per year in boys and girls, respectively. MHO phenotype was not associated with an increased risk of T2DM for both sexes. Adjusted HRs for MUO were [4.30 95% CI (1.48–12.43)] and [3.39 95% CI (1.78–6.45)] in boys and girls, respectively. MUNW phenotype was associated with an increased risk of T2DM only in boys. After adjustment for adulthood BMI, all the phenotypes for both sexes lost their significance, except for boys with MUNW phenotype [HR = 3.46 95% CI (1.15–10.45)]. Conclusions: Unhealthy obesity phenotypes; in contrast with MHO; had an increased risk of T2DM incidence, apart from girls with MUNW. After adjusting the adulthood BMI, all phenotypes turn insignificant, except for boys with MUNW. [ABSTRACT FROM AUTHOR]

Background: Long-term antithyroid drug therapy has become one of the options for treatment of Graves' hyperthyroidism. The aim of this study was to compare thyroid status in those who discontinued methimazole (MMI) treatment after 12.8 years with those who continued MMI as long as 24 years. Methods: Fifty nine patients with Graves' disease on long-term MMI for 14.2 ± 2.9 years were recruited; 32 patients (54%) decided to discontinue MMI and 27 (46%) preferred additional years of MMI treatment. All patients were followed for a mean of 6 additional years. Results: Of 27 patients who continued MMI up to 24 years, suppressed serum thyrotropin (TSH) was not observed in any patient after the seventh year of treatment. Serum free thyroxine, triiodothyronine, TSH and TSH receptor antibody concentrations remained normal up to the length of the study. Mean daily dose of MMI to maintain TSH in the reference range decreased gradually and reached to 2.8 ± 1.7 mg by 24 years of MMI treatment. No adverse reaction related to MMI occured during additional years of therapy. In 32 patients who discontinued MMI, hyperthyroidism relapsed in 6 patients (19%), one left follow-up and 25 (78%) remained euthyroid during the study. Conclusions: Long-term low dose MMI treatment may be a lifelong effective and safe therapeutic modality in patients with Graves' hyperthyroidism for prevention of relapse, if studies from other centers confirm findings of this research. Trial registration: IRCT201009224794N1, 2010-10-25. Retrospectively registered. https://www.irct.ir/trial/5143. [ABSTRACT FROM AUTHOR]

Background/Aims: We aimed to evaluate the association between change in thyroid function tests within the euthyroid range and body mass index (BMI) in persons with normal weight at baseline. Methods: This study investigated 1,100 normal-weight euthyroid persons in a population-based cohort study, Tehran Thyroid Study. BMI was calculated and serum concentrations of thyrotropin (TSH) and free T4 (FT4) were assayed at baseline and after 10 years of follow-up. We evaluated the relationship between thyroid and obesity based on 2 definitions for outcome: (1) a binary outcome as BMI <25 or ≥ 25 kg/m2, and (2) a multinomial outcome as normal BMI, overweight, and obese. Results: A total of 569 women and 531 men, aged 36.3 ± 13.5 years, were included. Modified Poisson regression analysis for binary outcome, after adjustment for age, sex, smoking, and antithyroid peroxidase antibody status, revealed a negative association between delta serum FT4 and follow-up BMI (relative risk 0.55 [95% CI 0.37–0.80]) without any significant association between change in serum TSH and follow-up BMI. However, in multinomial logistic regression analysis, we found no relationship between delta serum FT4 or TSH and follow-up BMI categories, for either overweight or obese vs. normal-weight participants. Conclusions: In normal-weight euthyroid individuals, changes in serum concentrations of FT4, but not TSH, may contribute to change in body weight. [ABSTRACT FROM AUTHOR]

Background: Data regarding the impact of different lipid measures on cardiovascular diseases (CVD) and mortality events is not consistent. We aimed to evaluate the relationship between different lipid parameters and incident CVD and mortality events in an Iranian population over a median follow-up of 11.9 years. Methods: The study was conducted on 2532 men and 2986 women aged ≥ 40 years. Multivariate adjusted hazard ratios (HRs), using age as time scale, were calculated for every 1 standard deviation (SD) increase in total cholesterol (TC), logarithm-transformed triglycerides (ln-TGs), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), non-HDL-C, TC/HDL-C and ln-TGs/HDL-C. Covariates included gender (female as reference), body mass index, education status, low physical activity, smoking, blood pressure status (normotension, prehypertension and hypertension), glucose tolerance status (normal glucose tolerance, prediabetes and diabetes) and lipid lowering drugs. The same analyses were also repeated for tertiles of all lipid measures. Considering the absence of interaction between gender and lipid parameters, we used a sex-adjusted analysis. For analyses of mortality events, prevalent CVD was adjusted as well (All p for interactions > 0.1). Results: A total of 789 new CVD events, 279 cardiovascular (CV) and 270 non-CV deaths occurred. In multivariate analysis, all lipid measures except HDL-C showed significant risk for new CVD events with HRs ranged from 1.14 to 1.27 for ln-TGs/HDL-C and LDL-C, respectively (all p-values ≤ 0.001). Considering CV mortality, there were significant positive associations between TC, LDL-C, non-HDL-C, TC/HDL-C and CV mortality events in sex-adjusted analysis; however after multivariate analysis, these associations attenuated and reached to null. Applying lipid measures as categorical variables, only TC displayed a positive association with CV mortality in multivariate analysis [TC ≥ 6.14 mmol/L: HR 1.43 (1.04-1.98)]. In multivariate analysis, there were negative significant associations between all lipid measures except HDL-C and non-CV mortality; every 1-SD increase in TC, LDL-C, non-HDL-C, ln-TGs,TC/HDL-C and ln-TGs/HDL-C was associated with 24, 25, 27, 19, 23 and 17 % decreased risk in non-CV mortality (all p-values ≤ 0.01). Conclusions: These findings indicate divergent associations of TC, LDL-C, non-HDL-C, TC/HDL-C, TGs and TGs/HDL-C with CVD vs non-CV mortality, demonstrating a higher risk for the former and lower risk for the latter. [ABSTRACT FROM AUTHOR]