Efficacy and Safety of Metformin and Atorvastatin Combination Therapy vs. Monotherapy with Either Drug in Type 2 Diabetes Mellitus and Dyslipidemia Patients (ATOMIC): Double-Blinded Randomized Controlled Trial.

Background: It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia. Methods: This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment. Results: After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. -0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (-55.20% vs. -7.69%, P<0.001) without previously unknown adverse drug events. Conclusion: The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin's preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.

Correction to: Sleep and Neuroimaging.

[This corrects the article DOI: 10.1007/s13139-020-00636-9.].

Trabecular Bone Score and Central Quantitative Computed Tomography for the Prediction of Vertebral Fragility Fractures in Postmenopausal Women.

BACKGROUND: We aimed to investigate whether densitometry results and volumetric bone mineral density (vBMD) can predict vertebral fragility fractures (VFF) in postmenopausal women. METHODS: We enrolled 271 postmenopausal women aged >45 years who visited our hospital for health check-ups between September 2016 and September 2017. The lumbar spine (LS) and femoral neck (FN) densitometry results and trabecular bone score (TBS) were calculated using dual energy X-ray absorptiometry. vBMD was assessed using central quantitative computed tomography (cQCT). Baseline and follow-up X-ray images were reviewed to evaluate thoracolumbar vertebral compression fractures (CFs), according to the Genant criteria. RESULTS: At baseline, 76 patients (28.0%) had CF. Additional or progressive fractures were noted in 26 participants (9.6%) with a median follow-up of 19.5 months. The median TBS and cQCT were significantly higher in participants without baseline CF than those with baseline CF (p<0.001). During the follow-up, Kaplan-Meier analysis showed that T-scores of the LS and FN <-2.5, degraded microarchitecture based on the TBS (≤1.200), and vBMD <80 mg/cm3 was significantly associated with future osteoporotic CF. The final multivariate Cox regression analysis showed that baseline CF and low TBS and vBMD were significant risk factors for future VFF. CONCLUSIONS: Participants with baseline CF and degraded microarchitecture had higher CF predisposition. Moreover, cQCT can predict future vertebral fractures.

Dopamine receptor and dopamine transporter in obesity: A meta-analysis.

The brain plays a major role in controlling the desire to eat. This meta-analysis aimed to assess the association between dopamine receptor (DR) availability and dopamine transporter (DAT) availability, measured using positron emission tomography, and obesity. We performed a systematic search of MEDLINE (from inception to November 2020) and EMBASE (from inception to November 2020) for articles published in English using the keywords "dopamine receptor," "dopamine transporter," "obesity," and "neuroimaging." Body mass index (BMI) and the corresponding binding potential (BPND ) were extracted from figures in each study using Engauge Digitizer, version 12.1, and plotted for radiopharmaceuticals and regions of interest (ROIs). Five studies involving 119 subjects with DR and five studies including 421 subjects with DAT were eligible for inclusion in this study. In overweight or obese subjects with BMI of 25 kg/m2 or higher, DR availability from 11 C-Racloprie was negatively associated with BMI. However, DR availability from 11 C-PHNO was positively associated with BMI. DAT ratio was calculated after dividing DAT availabilities of overweight/obese BMI with mean DAT availabilities of normal BMI. The association between DAT ratio and BMI was not significant regardless of radiopharmaceuticals. In conclusion, dopamine plays a main role in the reward system with regard to obesity. Overweight and obese subjects had negative association between DR availability from 11 C-Raclopride and BMI. However, the association of DR availability with BMI was dependent on radiopharmaceuticals. DAT availability did not show the significant relationship with BMI regardless of radiopharmaceuticals.

Hepatic Fat Quantification with the Multi-Material Decomposition Algorithm by Using Low-Dose Non-Contrast Material-Enhanced Dual-Energy Computed Tomography in a Prospectively Enrolled Cohort.

The early diagnosis of hepatic steatosis is important. No study has assessed hepatic fat quantification by using low-dose dual-energy computed tomography (CT). We assessed the accuracy of hepatic fat quantification using the multi-material decomposition (MMD) algorithm with low-dose non-contrast material-enhanced dual-energy CT. We retrospectively reviewed 33 prospectively enrolled patients who had undergone low-dose non-contrast material-enhanced dual-energy CT and magnetic resonance image (MRI) proton density fat fraction (PDFF) on the same day. Percentage fat volume fraction (FVF) images were generated using the MMD algorithm on the low-dose dual-energy CT data. We assessed the correlation between FVFs and MRI-PDFFs by using Spearman's rank correlation. With a 5% cutoff value of MRI-PDFF for fatty liver, a receiver operating characteristic (ROC) curve analysis was performed to identify the optimal criteria of FVF for diagnosing fatty liver. CTDIvol of CT was 2.94 mGy. FVF showed a strong correlation with MRI-PDFF (r = 0.756). The ROC curve analysis demonstrated that FVF ≥ 4.61% was the optimal cutoff for fatty liver. With this cutoff value for diagnosing the fatty liver on low-dose dual-energy CT, the sensitivity, specificity, and area under the curve were 90%, 100%, and 0.987, respectively. The MMD algorithm using low-dose non-contrast material-enhanced dual-energy CT is feasible for quantifying hepatic fat.

Heart Failure and Stroke Risks in Users of Liothyronine With or Without Levothyroxine Compared with Levothyroxine Alone: A Propensity Score-Matched Analysis.

Background: Combination therapy with liothyronine (LT3) and levothyroxine (LT4) is used in patients with persistent symptoms, despite being administered an adequate dose of LT4. LT3 may also be used in some thyroid cancer patients preparing for radioactive iodine therapy. However, there is a controversy regarding the safety of LT3 use, and there has been no definite evidence of long-term safety of LT3 therapy in Asian populations. The aim of this study was to examine the long-term safety of LT3 therapy using the Common Data Model (CDM). Methods: We conducted a retrospective multicenter study across four hospital databases encoded in the Observational Medical Outcomes Partnership (OMOP) CDM. LT3 users were defined as those who received an LT3 prescription for at least 90 days (with or without LT4), and their safety outcomes were compared with those in LT4-only users after 1:4 propensity score matching. Safety outcomes included the incidences of osteoporosis, cardiovascular disease, cancer, anxiety disorder, and mood disorder. Results: We identified 1434 LT3 users and 3908 LT4-only users. There was a statistically significant difference in the incidence rate of safety outcomes between LT3 users and LT4-only users. The risks of heart failure (incidence rate ratio [IRR] = 1.664, 95% confidence interval [95% CI] 1.002-2.764, p = 0.049) and stroke (IRR = 1.757, CI 1.073-2.877, p = 0.025) were higher in LT3 users than in LT4-only users. When subgroup analysis was performed according to the presence/absence of thyroid cancer history and duration of thyroid hormone replacement, the risk of heart failure was higher in LT3 users with a history of thyroid cancer and those who underwent ≥52 weeks of LT3 therapy. In addition, the risk of stroke was higher in LT3 users without thyroid cancer history and those who underwent ≥52 weeks of LT3 therapy. Conclusions: The use of LT3 was associated with increased incidence of heart failure and stroke in patients with a longer duration of LT3 use and history of thyroid cancer. Therefore, clinicians should consider the risk of heart failure and stroke in thyroid cancer patients with long-term use of LT3. These findings require confirmation in other populations.

Multi-omics analysis revealed TEK and AXIN2 are potential biomarkers in multifocal papillary thyroid cancer.

BACKGROUND: Papillary thyroid carcinoma (PTC), the most common endocrine cancer, accounts for 80-85% of all malignant thyroid tumors. This study focused on identifying targets that affect the multifocality of PTC. In a previous study, we determined 158 mRNAs related to multifocality in BRAF-mutated PTC using The Cancer Genome Atlas. METHODS: We used multi-omics data (miRNAs and mRNAs) to identify the regulatory mechanisms of the investigated mRNAs. miRNA inhibitors were used to determine the relationship between mRNAs and miRNAs. We analyzed the target protein levels in patient sera using ELISA and immunohistochemical staining of patients' tissues. RESULTS: We identified 44 miRNAs that showed a negative correlation with mRNA expression. Using in vitro experiments, we identified four miRNAs that inhibit TEK and/or AXIN2 among the target mRNAs. We also showed that the downregulation of TEK and AXIN2 decreased the proliferation and migration of BRAF ( +) PTC cells. To evaluate the diagnostic ability of multifocal PTC, we examined serum TEK or AXIN2 in unifocal and multifocal PTC patients using ELISA, and showed that the serum TEK in multifocal PTC patients was higher than that in the unifocal PTC patients. The immunohistochemical study showed higher TEK and AXIN2 expression in multifocal PTC than unifocal PTC. CONCLUSIONS: Both TEK and AXIN2 play a potential role in the multifocality of PTC, and serum TEK may be a diagnostic marker for multifocal PTC.

A double-blind, Randomized controlled trial on glucose-lowering EFfects and safety of adding 0.25 or 0.5 mg lobeglitazone in type 2 diabetes patients with INadequate control on metformin and dipeptidyl peptidase-4 inhibitor therapy: REFIND study.

AIMS: To compare the efficacy and safety of adding low-dose lobeglitazone (0.25 mg/day) or standard-dose lobeglitazone (0.5 mg/day) to patients with type 2 diabetes mellitus (T2DM) with inadequate glucose control on metformin and dipeptidyl peptidase (DPP4) inhibitor therapy. MATERIALS AND METHODS: In this phase 4, multicentre, double-blind, randomized controlled, non-inferiority trial, patients with T2DM insufficiently controlled by metformin and DPP4 inhibitor combination therapy were randomized to receive either low-dose or standard-dose lobeglitazone. The primary endpoint was non-inferiority of low-dose lobeglitazone in terms of glycaemic control, expressed as the difference in mean glycated haemoglobin levels at week 24 relative to baseline values and compared with standard-dose lobeglitazone, using 0.5% non-inferiority margin. RESULTS: At week 24, the mean glycated haemoglobin levels were 6.87 ± 0.54% and 6.68 ± 0.46% in low-dose and standard-dose lobeglitazone groups, respectively (p = .031). The between-group difference was 0.18% (95% confidence interval 0.017-0.345), showing non-inferiority of the low-dose lobeglitazone. Mean body weight changes were significantly greater in the standard-dose group (1.36 ± 2.23 kg) than in the low-dose group (0.50 ± 1.85 kg) at week 24. The changes in HOMA-IR, lipid profile and liver enzyme levels showed no significant difference between the groups. Overall treatment-emergent adverse events (including weight gain, oedema and hypoglycaemia) occurred more frequently in the standard-dose group. CONCLUSIONS: Adding low-dose lobeglitazone to metformin and DPP4 inhibitor combination resulted in a non-inferior glucose-lowering outcome and fewer adverse events compared with standard-dose lobeglitazone. Therefore, low-dose lobeglitazone might be one option for individualized strategy in patients with T2DM.