Assessment of hepatic transporter function in rats using dynamic gadoxetate-enhanced MRI: a reproducibility study.

OBJECTIVE: Previous studies have revealed a substantial between-centre variability in DCE-MRI biomarkers of hepatocellular function in rats. This study aims to identify the main sources of variability by comparing data measured at different centres and field strengths, at different days in the same subjects, and over the course of several months in the same centre. MATERIALS AND METHODS: 13 substudies were conducted across three facilities on two 4.7 T and two 7 T scanners using a 3D spoiled gradient echo acquisition. All substudies included 3-6 male Wistar-Han rats each, either scanned once with vehicle (n = 76) or twice with either vehicle (n = 19) or 10 mg/kg of rifampicin (n = 13) at follow-up. Absolute values, between-centre reproducibility, within-subject repeatability, detection limits, and effect sizes were derived for hepatocellular uptake rate (Ktrans) and biliary excretion rate (kbh). Sources of variability were identified using analysis of variance and stratification by centre, field strength, and time period. RESULTS: Data showed significant differences between substudies of 31% for Ktrans (p = 0.013) and 43% for kbh (p < 0.001). Within-subject differences were substantially smaller for kbh (8%) but less so for Ktrans (25%). Rifampicin-induced inhibition was safely above the detection limits, with an effect size of 75 ± 3% in Ktrans and 67 ± 8% in kbh. Most of the variability in individual data was accounted for by between-subject (Ktrans = 23.5%; kbh = 42.5%) and between-centre (Ktrans = 44.9%; kbh = 50.9%) variability, substantially more than the between-day variation (Ktrans = 0.1%; kbh = 5.6%). Significant differences in kbh were found between field strengths at the same centre, between centres at the same field strength, and between repeat experiments over 2 months apart in the same centre. DISCUSSION: Between-centre bias caused by factors such as hardware differences, subject preparations, and operator dependence is the main source of variability in DCE-MRI of liver function in rats, closely followed by biological between-subject differences. Future method development should focus on reducing these sources of error to minimise the sample sizes needed to detect more subtle levels of inhibition.

Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol.

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721.

Magnetic Resonance Imaging in Clinical Trials of Diabetic Kidney Disease.

Chronic kidney disease (CKD) associated with diabetes mellitus (DM) (known as diabetic kidney disease, DKD) is a serious and growing healthcare problem worldwide. In DM patients, DKD is generally diagnosed based on the presence of albuminuria and a reduced glomerular filtration rate. Diagnosis rarely includes an invasive kidney biopsy, although DKD has some characteristic histological features, and kidney fibrosis and nephron loss cause disease progression that eventually ends in kidney failure. Alternative sensitive and reliable non-invasive biomarkers are needed for DKD (and CKD in general) to improve timely diagnosis and aid disease monitoring without the need for a kidney biopsy. Such biomarkers may also serve as endpoints in clinical trials of new treatments. Non-invasive magnetic resonance imaging (MRI), particularly multiparametric MRI, may achieve these goals. In this article, we review emerging data on MRI techniques and their scientific, clinical, and economic value in DKD/CKD for diagnosis, assessment of disease pathogenesis and progression, and as potential biomarkers for clinical trial use that may also increase our understanding of the efficacy and mode(s) of action of potential DKD therapeutic interventions. We also consider how multi-site MRI studies are conducted and the challenges that should be addressed to increase wider application of MRI in DKD.

Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug-Drug Interactions in Rats.

Gadoxetate, a magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 and multidrug resistance-associated protein 2. Six drugs, with varying degrees of transporter inhibition, were used to assess gadoxetate dynamic contrast enhanced MRI biomarkers for transporter inhibition in rats. Prospective prediction of changes in gadoxetate systemic and liver AUC (AUCR), resulting from transporter modulation, were performed by physiologically-based pharmacokinetic (PBPK) modelling. A tracer-kinetic model was used to estimate rate constants for hepatic uptake (khe), and biliary excretion (kbh). The observed median fold-decreases in gadoxetate liver AUC were 3.8- and 1.5-fold for ciclosporin and rifampicin, respectively. Ketoconazole unexpectedly decreased systemic and liver gadoxetate AUCs; the remaining drugs investigated (asunaprevir, bosentan, and pioglitazone) caused marginal changes. Ciclosporin decreased gadoxetate khe and kbh by 3.78 and 0.09 mL/min/mL, while decreases for rifampicin were 7.20 and 0.07 mL/min/mL, respectively. The relative decrease in khe (e.g., 96% for ciclosporin) was similar to PBPK-predicted inhibition of uptake (97-98%). PBPK modelling correctly predicted changes in gadoxetate systemic AUCR, whereas underprediction of decreases in liver AUCs was evident. The current study illustrates the modelling framework and integration of liver imaging data, PBPK, and tracer-kinetic models for prospective quantification of hepatic transporter-mediated DDI in humans.

Multiparametric magnetic resonance imaging allows non-invasive functional and structural evaluation of diabetic kidney disease.

Background: We sought to develop a novel non-contrast multiparametric MRI (mpMRI) protocol employing several complementary techniques in a single scan session for a comprehensive functional and structural evaluation of diabetic kidney disease (DKD). Methods: In the cross-sectional part of this prospective observational study, 38 subjects ages 18‒79 years with type 2 diabetes and DKD [estimated glomerular filtration rate (eGFR) 15‒60 mL/min/1.73 m2] and 20 age- and gender-matched healthy volunteers (HVs) underwent mpMRI. Repeat mpMRI was performed on 23 DKD subjects and 10 HVs. By measured GFR (mGFR), 2 DKD subjects had GFR stage G2, 16 stage G3 and 20 stage G4/G5. A wide range of MRI biomarkers associated with kidney haemodynamics, oxygenation and macro/microstructure were evaluated. Their optimal sensitivity, specificity and repeatability to differentiate diabetic versus healthy kidneys and categorize various stages of disease as well as their correlation with mGFR/albuminuria was assessed. Results: Several MRI biomarkers differentiated diabetic from healthy kidneys and distinct GFR stages (G3 versus G4/G5); mean arterial flow (MAF) was the strongest predictor (sensitivity 0.94 and 1.0, specificity 1.00 and 0.69; P = .04 and .004, respectively). Parameters significantly correlating with mGFR were specific measures of kidney haemodynamics, oxygenation, microstructure and macrostructure, with MAF being the strongest univariate predictor (r = 0.92; P < .0001). Conclusions: A comprehensive and repeatable non-contrast mpMRI protocol was developed that, as a single, non-invasive tool, allows functional and structural assessment of DKD, which has the potential to provide valuable insights into underlying pathophysiology, disease progression and analysis of efficacy/mode of action of therapeutic interventions in DKD.

Fatty acids in multiple circulating lipid fractions reflects the composition of liver triglycerides in humans.

BACKGROUND AND AIMS: Fatty acids (e.g. 16:1n-7) and desaturase indices (e.g. stearoyl-CoA desaturase, SCD) in plasma cholesteryl esters (CE) and phospholipids (PL) are used as biomarkers of dietary fat quality and lipid metabolism and are associated with disease outcomes. Endogenously produced circulating fatty acids are believed to reflect composition of the liver, yet little data exist to support such relationship. We investigated associations between circulating fatty acids and fatty acids within the liver. METHODS: Liver biopsies and blood were collected from n = 60 patients with non-alcoholic fatty liver disease. Fatty acids in CE, PL and triglycerides (TG) in plasma and liver were analyzed using gas chromatography. Associations were assessed using Spearman rank correlations. RESULTS: Overall, fatty acids and desaturase indices in plasma PL and TG showed moderate-strong correlations with fatty acids and desaturase indices in corresponding lipid fractions in liver. For plasma CE, 16:1n-7 and SCD were correlated with 16:1n-7 and SCD in liver CE. Noteworthy, fatty acids in plasma CE and PL also showed moderate-strong correlations with fatty acids in liver TG (e.g. r = 0.82-0.87 for 16:1n-7 and r = 0.77 for SCD). CONCLUSION: We demonstrate that fatty acids in circulating lipid fractions, including CE, TG and PL, reflects the composition of liver TG in humans, suggesting that circulating fatty acids might be useful biomarkers for the fatty acid composition of the liver. As liver tissue is rarely available in cohort studies, our findings could enhance our understanding of plasma fatty acids as markers of hepatic lipid metabolism and their links to metabolic diseases.

The Combination of MR Elastography and Proton Density Fat Fraction Improves Diagnosis of Nonalcoholic Steatohepatitis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide. It is subdivided into nonalcoholic fatty liver (NAFL) and the more aggressive form, nonalcoholic steatohepatitis (NASH), which carries a higher risk of developing fibrosis and cirrhosis. There is currently no reliable non-invasive method for differentiating NASH from NAFL. PURPOSE: To investigate the ability of magnetic resonance imaging (MRI)-based imaging biomarkers to diagnose NASH and moderate fibrosis as well as assess their repeatability. STUDY TYPE: Prospective. SUBJECTS: Sixty-eight participants (41% women) with biopsy-proven NAFLD (53 NASH and 15 NAFL). Thirty participants underwent a second MRI in order to assess repeatability. FIELD STRENGTH/SEQUENCE: 3.0 T; MR elastography (MRE) (a spin-echo echo-planar imaging [SE-EPI] sequence with motion-encoding gradients), MR proton density fat fraction (PDFF) and R2* mapping (a multi-echo three-dimensional gradient-echo sequence), T1 mapping (a single-point saturation-recovery technique), and diffusion-weighted imaging (SE-EPI sequence). ASSESSMENT: Quantitative MRI measurements were obtained and assessed alone and in combination with biochemical markers (cytokeratin-18 [CK18] M30, alanine transaminase [ALT], and aspartate transaminase [AST]) using logistic regression models. Models that could differentiate between NASH and NAFL and between moderate to advanced fibrosis (F2-4) and no or mild fibrosis (F0-1), based on the histopathological results, were identified. STATISTICAL TESTS: Independent samples t-test, Pearson's chi-squared test, area under the receiver operating characteristic curve (AUROC), Spearman's correlation, intra-individual coefficient of variation, and intraclass correlation coefficient (ICC). Statistical significance was set at P < 0.05. RESULTS: There was a significant difference between the NASH and NAFL groups with liver stiffness assessed with MRE, CK18 M30, and ALT, with an AUROC of 0.74, 0.76, and 0.70, respectively. Both MRE and PDFF contributed significantly to a bivariate model for diagnosing NASH (AUROC = 0.84). MRE could significantly differentiate between F2-4 and F0-1 (AUROC = 0.74). A model combining MRE with AST improved the diagnosis of F2-4 (AUROC = 0.83). The ICC for repeatability was 0.94 and 0.99 for MRE and PDFF, respectively. DATA CONCLUSION: MRE can potentially diagnose NASH and differentiate between fibrosis stages. Combining MRE with PDFF improves the diagnosis of NASH. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Long-term effects of dapagliflozin plus saxagliptin versus glimepiride on a background of metformin in patients with type 2 diabetes: Results of a 104-week extension to a 52-week randomized, phase 3 study and liver fat MRI substudy.

AIM: To report the results of a 104-week extension to a 52-week study in which dapagliflozin plus saxagliptin (DAPA+SAXA) improved glycaemic control, liver fat and metabolic variables compared with glimepiride (GLIM) in participants with type 2 diabetes (T2D) receiving background metformin. MATERIALS AND METHODS: This extension to a 52-week global, multicentre, parallel-group, active-controlled, double-blind study (NCT02419612) continued randomized participants (1:1) on DAPA+SAXA (10/5 mg) plus placebo, or GLIM (1-6 mg) plus placebo, once daily. Eligible participants were aged ≥18 years, had T2D (glycated haemoglobin [HbA1c] 58.5-91.3 mmol/mol [7.5%-10.5%]), and a body mass index of 20.0 to 45.0 kg/m2 , and were receiving metformin (MET; ≥1500 mg/d). Key outcomes were: requirement for treatment intensification, based on HbA1c ≥53 mmol/mol (7%); achieving therapeutic glycaemic response; and changes in adipose tissue and liver fat on magnetic resonance imaging in a substudy. RESULTS: Overall, 382 participants entered and 338 completed the 104-week extension period (MRI substudy, n = 82). The need for treatment intensification during the 156-week period was lower for DAPA+SAXA+MET (37.0%) than GLIM+MET (55.6%; hazard ratio 0.52, 95% confidence interval [CI] 0.39-0.68; P < 0.001). At week 156, 21.4% of DAPA+SAXA+MET versus 11.7% of GLIM+MET participants achieved therapeutic glycaemic response (HbA1c <53 mmol/mol; odds ratio 2.1, 95% CI 1.23-3.42; P = 0.006). DAPA+SAXA+MET led to greater adjusted mean reductions from baseline in liver fat and visceral and subcutaneous adipose tissue volumes versus GLIM+MET at week 122 (least-squares mean difference from GLIM+MET -4.89%, -0.41 L and -0.44 L, respectively; nominal P values ≤ 0.008). Safety was consistent with that of the monocomponents. CONCLUSIONS: Overall, glycaemic control, metabolic benefits and efficacy were better maintained with DAPA+SAXA+MET than with GLIM+MET in T2D.

Consensus-Based Technical Recommendations for Clinical Translation of Renal Phase Contrast MRI.

BACKGROUND: Phase-contrast (PC) MRI is a feasible and valid noninvasive technique to measure renal artery blood flow, showing potential to support diagnosis and monitoring of renal diseases. However, the variability in measured renal blood flow values across studies is large, most likely due to differences in PC-MRI acquisition and processing. Standardized acquisition and processing protocols are therefore needed to minimize this variability and maximize the potential of renal PC-MRI as a clinically useful tool. PURPOSE: To build technical recommendations for the acquisition, processing, and analysis of renal 2D PC-MRI data in human subjects to promote standardization of renal blood flow measurements and facilitate the comparability of results across scanners and in multicenter clinical studies. STUDY TYPE: Systematic consensus process using a modified Delphi method. POPULATION: Not applicable. SEQUENCE FIELD/STRENGTH: Renal fast gradient echo-based 2D PC-MRI. ASSESSMENT: An international panel of 27 experts from Europe, the USA, Australia, and Japan with 6 (interquartile range 4-10) years of experience in 2D PC-MRI formulated consensus statements on renal 2D PC-MRI in two rounds of surveys. Starting from a recently published systematic review article, literature-based and data-driven statements regarding patient preparation, hardware, acquisition protocol, analysis steps, and data reporting were formulated. STATISTICAL TESTS: Consensus was defined as ≥75% unanimity in response, and a clear preference was defined as 60-74% agreement among the experts. RESULTS: Among 60 statements, 57 (95%) achieved consensus after the second-round survey, while the remaining three showed a clear preference. Consensus statements resulted in specific recommendations for subject preparation, 2D renal PC-MRI data acquisition, processing, and reporting. DATA CONCLUSION: These recommendations might promote a widespread adoption of renal PC-MRI, and may help foster the set-up of multicenter studies aimed at defining reference values and building larger and more definitive evidence, and will facilitate clinical translation of PC-MRI. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

Randomised clinical trial: semaglutide versus placebo reduced liver steatosis but not liver stiffness in subjects with non-alcoholic fatty liver disease assessed by magnetic resonance imaging.

BACKGROUND: Glucagon-like peptide-1 receptor agonists may be a treatment option in patients with non-alcoholic fatty liver disease (NAFLD). AIMS: To investigate the effects of semaglutide on liver stiffness and liver fat in subjects with NAFLD using non-invasive magnetic resonance imaging (MRI) methods. METHODS: This randomised, double-blind, placebo-controlled trial enrolled subjects with liver stiffness 2.50-4.63 kPa by magnetic resonance elastography (MRE) and liver steatosis ≥10% by MRI proton density fat fraction (MRI-PDFF). The primary endpoint was change from baseline to week 48 in liver stiffness assessed by MRE. RESULTS: Sixty-seven subjects were randomised to once-daily subcutaneous semaglutide 0.4 mg (n = 34) or placebo (n = 33). Change from baseline in liver stiffness was not significantly different between semaglutide and placebo at week 48 (estimated treatment ratio 0.96 (95% CI 0.89, 1.03; P = 0.2798); significant differences in liver stiffness were not observed at weeks 24 or 72. Reductions in liver steatosis were significantly greater with semaglutide (estimated treatment ratios: 0.70 [0.59, 0.84], P = 0.0002; 0.47 [0.36, 0.60], P < 0.0001; and 0.50 [0.39, 0.66], P < 0.0001) and more subjects achieved a ≥ 30% reduction in liver fat content with semaglutide at weeks 24, 48 and 72, (all P < 0.001). Decreases in liver enzymes, body weight and HbA1c were also observed with semaglutide. CONCLUSIONS: The change in liver stiffness in subjects with NAFLD was not significantly different between semaglutide and placebo. However, semaglutide significantly reduced liver steatosis compared with placebo which, together with improvements in liver enzymes and metabolic parameters, suggests a positive impact on disease activity and metabolic profile. ClinicalTrials.gov identifier: NCT03357380.

Hepatic Unsaturated Fatty Acids Are Linked to Lower Degree of Fibrosis in Non-alcoholic Fatty Liver Disease.

Background: The hepatic lipidome of patients with early stages of non-alcoholic fatty liver disease (NAFLD) has been fairly well-explored. However, studies on more progressive forms of NAFLD, i.e., liver fibrosis, are limited. Materials and methods: Liver fatty acids were determined in cholesteryl esters (CE), phospholipids (PL), and triacylglycerols (TAG) by gas chromatography. Cross-sectional associations between fatty acids and biopsy-proven NAFLD fibrosis (n = 60) were assessed using multivariable logistic regression models. Stages of fibrosis were dichotomized into none-mild (F0-1) or significant fibrosis (F2-4). Models were adjusted for body-mass index (BMI), age and patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409) (I148M) genotype. A secondary analysis examined whether associations from the primary analysis could be confirmed in the corresponding plasma lipid fractions. Results: PL behenic acid (22:0) was directly associated [OR (95% CI): 1.86 (1.00, 3.45)] whereas PL docosahexaenoic acid (22:6n-3) [OR (95% CI): 0.45 (0.23, 0.89)], TAG oleic acid (18:1n-9) [OR (95% CI): 0.52 (0.28, 0.95)] and 18:1n-9 and vaccenic acid (18:1n-7) (18:1) [OR (95% CI): 0.52 (0.28, 0.96)] were inversely associated with liver fibrosis. In plasma, TAG 18:1n-9 [OR (95% CI): 0.55 (0.31, 0.99)], TAG 18:1 [OR (95% CI): 0.54 (0.30, 0.97)] and PL 22:0 [OR (95% CI): 0.46 (0.25, 0.86)] were inversely associated with liver fibrosis. Conclusion: Higher TAG 18:1n-9 levels were linked to lower fibrosis in both liver and plasma, possibly reflecting an altered fatty acid metabolism. Whether PL 22:6n-3 has a protective role, together with a potentially adverse effect of hepatic 22:0, on liver fibrosis warrants large-scale studies.

Clinical Characteristics of a Non-Alcoholic Fatty Liver Disease Population Across the Fibrosis Spectrum Measured by Magnetic Resonance Elastography: Analysis of Screening Data.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD), one of the most common liver diseases, is associated with liver-related complications and metabolic comorbidities. The phenotype is wide, ranging from simple steatosis to non-alcoholic steatohepatitis with advanced fibrosis. In this analysis of a phase 1 trial, clinical characteristics of screened subjects with NAFLD were studied according to the extent of fibrosis assessed using magnetic resonance elastography (MRE). METHODS: One hundred ninety-four subjects with body mass index (BMI) of 25-40 kg/m2 and suspected NAFLD were assessed by MRE and grouped by MRE thresholds as a proxy for fibrosis staging (groups 0-4). Data were summarized by group levels, and correlation analyses between MRE values and clinical parameters (including magnetic resonance imaging-proton density fat fraction) were performed. RESULTS: Most subjects had MRE values in the lower range (groups 0-1; N = 148). Type 2 diabetes (T2D) and BMI > 35 kg/m2 were more frequent in groups with higher than lower MRE values. Subjects in the highest MRE groups also tended to be older and have higher liver enzyme concentrations compared with lower MRE groups. No, or weak, correlations were found between MRE values and clinical parameters (all r values ≤ 0.45). CONCLUSIONS: There was considerable variation and overlap in clinical characteristics across the spectrum of liver stiffness. Although groups with high MRE values generally included more subjects with T2D and obesity, and had higher age and concentrations of liver enzymes, the clinical characteristics did not strongly correlate with MRE scores in this population. TRIAL REGISTRATION: Registered on Clinicaltrials.gov on November 29, 2017 (NCT03357380).

HEROIC: a 5-year observational cohort study aimed at identifying novel factors that drive diabetic kidney disease: rationale and study protocol.

INTRODUCTION: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease worldwide and a major cause of premature mortality in diabetes mellitus (DM). While improvements in care have reduced the incidence of kidney disease among those with DM, the increasing prevalence of DM means that the number of patients worldwide with DKD is increasing. Improved understanding of the biology of DKD and identification of novel therapeutic targets may lead to new treatments. A major challenge to progress has been the heterogeneity of the DKD phenotype and renal progression. To investigate the heterogeneity of DKD we have set up The East and North London Diabetes Cohort (HEROIC) Study, a secondary care-based, multiethnic observational study of patients with biopsy-proven DKD. Our primary objective is to identify histological features of DKD associated with kidney endpoints in a cohort of patients diagnosed with type 1 and type 2 DM, proteinuria and kidney impairment. METHODS AND ANALYSIS: HEROIC is a longitudinal observational study that aims to recruit 500 patients with DKD at high-risk of renal and cardiovascular events. Demographic, clinical and laboratory data will be collected and assessed annually for 5 years. Renal biopsy tissue will be collected and archived at recruitment. Blood and urine samples will be collected at baseline and during annual follow-up visits. Measured glomerular filtration rate (GFR), echocardiography, retinal optical coherence tomography angiography and kidney and cardiac MRI will be performed at baseline and twice more during follow-up. The study is 90% powered to detect an association between key histological and imaging parameters and a composite of death, renal replacement therapy or a 30% decline in estimated GFR. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Bloomsbury Research Ethics Committee (REC 18-LO-1921). Any patient identifiable data will be stored on a password-protected National Health Services N3 network with full audit trail. Anonymised imaging data will be stored in a ISO27001-certificated data warehouse.Results will be reported through peer-reviewed manuscripts and conferences and disseminated to participants, patients and the public using web-based and social media engagement tools as well as through public events.

Dapagliflozin plus saxagliptin add-on to metformin reduces liver fat and adipose tissue volume in patients with type 2 diabetes.

AIM: To assess the effects of dapagliflozin plus saxagliptin plus metformin versus glimepiride plus metformin on liver fat (proton density fat fraction) and visceral and subcutaneous adipose tissue volumes over 52 weeks of treatment. MATERIALS AND METHODS: This was a magnetic resonance imaging substudy of a 52-week, multicentre, randomized, double-blind, parallel-group trial that evaluated the efficacy and safety of dapagliflozin 10 mg/day plus saxagliptin 5 mg/day versus titrated glimepiride 1-6 mg (1, 2, 3, 4 or 6 mg) in 82 patients with type 2 diabetes (HbA1c 7.5%-10.5%) on metformin ≥1500 mg/day background. Analyses were exploratory and not controlled for multiplicity; P-values are nominal. RESULTS: Magnetic resonance imaging was performed on 59 patients; liver fat and adipose tissue volumes were analysed for 59 and 57 patients, respectively. There was a significant >30% reduction from baseline in liver fat (P = 0.007) and >10% reduction in adipose tissue volumes (P < 0.01) with dapagliflozin plus saxagliptin plus metformin at week 52 versus glimepiride plus metformin. In the full-study population, dapagliflozin plus saxagliptin plus metformin decreased body weight and serum alanine aminotransferase and aspartate aminotransferase levels over 52 weeks. CONCLUSIONS: Dapagliflozin plus saxagliptin significantly decreased liver fat and adipose tissue volume versus glimepiride, and reduced serum liver enzyme levels, indicating a favourable metabolic profile of dapagliflozin plus saxagliptin in patients with type 2 diabetes on metformin therapy.

Drug-induced myocardial dysfunction - recommendations for assessment in clinical and pre-clinical studies.

Introduction: Drug-induced myocardial dysfunction is an important safety concern during drug development. Oncology compounds can cause myocardial dysfunction, leading to decreased left ventricular ejection fraction and heart failure via several mechanisms. Cardiovascular imaging has a major role in the early detection and monitoring of cardiotoxicity. Echocardiography is the method of choice because of its widespread availability, low cost, and absence of radiation exposure. Cardiac magnetic resonance imaging can provide better reliability, reproducibility, and accuracy in the detection of drug-induced myocardial dysfunction. In addition, it enables assessment of myocardial edema, fibrosis, and necrosis. Cardiac serologic biomarkers such as troponins and B-type natriuretic peptides are used in combination with imaging during drug development. This article provides a general overview of each imaging modality and practical guidance for early detection and monitoring of cardiotoxicity.Areas covered: Cardiovascular imaging modalities and cardiac biomarkers for monitoring of cardiac function and early detection of drug-induced myocardial dysfunction in drug development.Expert opinion: Some new drugs especially in the oncology field, can cause myocardial dysfunction. Depending on the strength of pre-clinical or clinical data, CV imaging modalities and cardiac biomarkers play an important role in the early detection and mitigation plans for such drugs during their development.

Consensus-based technical recommendations for clinical translation of renal T1 and T2 mapping MRI.

To develop technical recommendations on the acquisition and post-processing of renal longitudinal (T1) and transverse (T2) relaxation time mapping. A multidisciplinary panel consisting of 18 experts in the field of renal T1 and T2 mapping participated in a consensus project, which was initiated by the European Cooperation in Science and Technology Action PARENCHIMA CA16103. Consensus recommendations were formulated using a two-step modified Delphi method. The first survey consisted of 56 items on T1 mapping, of which 4 reached the pre-defined consensus threshold of 75% or higher. The second survey was expanded to include both T1 and T2 mapping, and consisted of 54 items of which 32 reached consensus. Recommendations based were formulated on hardware, patient preparation, acquisition, analysis and reporting. Consensus-based technical recommendations for renal T1 and T2 mapping were formulated. However, there was considerable lack of consensus for renal T1 and particularly renal T2 mapping, to some extent surprising considering the long history of relaxometry in MRI, highlighting key knowledge gaps that require further work. This paper should be regarded as a first step in a long-term evidence-based iterative process towards ever increasing harmonization of scan protocols across sites, to ultimately facilitate clinical implementation.

Repeatability and reproducibility of longitudinal relaxation rate in 12 small-animal MRI systems.

BACKGROUND: Many translational MR biomarkers derive from measurements of the water proton longitudinal relaxation rate R1, but evidence for between-site reproducibility of R1 in small-animal MRI is lacking. OBJECTIVE: To assess R1 repeatability and multi-site reproducibility in phantoms for preclinical MRI. METHODS: R1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1-13 days. R1 was analysed in three different regions of interest, giving 360 measurements in total. Root-mean-square repeatability and reproducibility coefficients of variation (CoV) were calculated. Propagation of reproducibility errors into 21 translational MR measurements and biomarkers was estimated. Relaxivities were calculated. Dynamic signal stability was also measured. RESULTS: CoV for day-to-day repeatability (N = 180 regions of interest) was 2.34% and for between-centre reproducibility (N = 9 centres) was 1.43%. Mostly, these do not propagate to biologically significant between-centre error, although a few R1-based MR biomarkers were found to be quite sensitive even to such small errors in R1, notably in myocardial fibrosis, in white matter, and in oxygen-enhanced MRI. The relaxivity of aqueous Ni2+ in 2% agarose varied between 0.66 s-1 mM-1 at 3 T and 0.94 s-1 mM-1 at 11.7T. INTERPRETATION: While several factors affect the reproducibility of R1-based MR biomarkers measured preclinically, between-centre propagation of errors arising from intrinsic equipment irreproducibility should in most cases be small. However, in a few specific cases exceptional efforts might be required to ensure R1-reproducibility.