Ethnic Disparities in Lipid Metabolism and Clinical Outcomes between Dutch South Asians and Dutch White Caucasians with Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) poses a higher risk for complications in South Asian individuals compared to other ethnic groups. To shed light on potential mediating factors, we investigated lipidomic changes in plasma of Dutch South Asians (DSA) and Dutch white Caucasians (DwC) with and without T2DM and explore their associations with clinical features. Using a targeted quantitative lipidomics platform, monitoring over 1000 lipids across 17 classes, along with 1H NMR based lipoprotein analysis, we studied 51 healthy participants (21 DSA, 30 DwC) and 92 T2DM patients (47 DSA, 45 DwC) from the MAGNetic resonance Assessment of VICTOza efficacy in the Regression of cardiovascular dysfunction in type 2 dIAbetes mellitus (MAGNA VICTORIA) study. This comprehensive mapping of the circulating lipidome allowed us to identify relevant lipid modules through unbiased weighted correlation network analysis, as well as disease and ethnicity related key mediatory lipids. Significant differences in lipidomic profiles, encompassing various lipid classes and species, were observed between T2DM patients and healthy controls in both the DSA and DwC populations. Our analyses revealed that healthy DSA, but not DwC, controls already exhibited a lipid profile prone to develop T2DM. Particularly, in DSA-T2DM patients, specific lipid changes correlated with clinical features, particularly diacylglycerols (DGs), showing significant associations with glycemic control and renal function. Our findings highlight an ethnic distinction in lipid modules influencing clinical outcomes in renal health. We discover distinctive ethnic disparities of the circulating lipidome and identify ethnicity-specific lipid markers. Jointly, our discoveries show great potential as personalized biomarkers for the assessment of glycemic control and renal function in DSA-T2DM individuals.

MR Assessed Changes of Renal Sinus Fat in Response to Glucose Regulation in West European and South Asian Patients With Type 2 Diabetes.

BACKGROUND: Ethnic differences in the progression and outcome of diabetic kidney disease (DKD) remain to be elucidated. MRI-quantified renal sinus fat volume could be a potential biomarker to help investigate the changes of DKD risk in response to glucose regulation. PURPOSE: To evaluate whether the effect of glucose-lowering treatment on renal sinus fat volume differed in West Europeans (WE) compared to South Asians (SA), and whether ethnic-related difference exists regarding the effect of liraglutide on renal sinus fat. STUDY TYPE: Retrospective. POPULATION: Ninety-three patients with type 2 diabetes mellitus, including 47 WE (27 males) aged 59.3 ± 6.5 years, and 46 SA (19 males) aged 54.4 ± 9.8 years. FIELD STRENGTH/SEQUENCE: 3.0 T dual-echo fast gradient-echo pulse sequence using two-point Dixon technique with a phase-correction algorithm. ASSESSMENT: Changes of renal sinus fat volume were measured by a radiologist (LL) with 4-years' experience, and were compared between the two ethnic groups, together with glycemic level, metabolic risk factors and renal function. The effects of liraglutide were assessed. STATISTICAL TESTS: Normality of the data was visually evaluated by histograms and Q-Q plots. Within-group and between-group differences were analyzed using paired t-tests and analysis of covariance. Associations were analyzed by person's correlation and multiple linear regression models. RESULTS: Renal sinus fat decreased in SA patients (Δ% = -7.6% ± 14.8%), but increased in WE patients (Δ% = 5.0% ± 13.1%), with a significant difference between the two ethnic groups. In the WE group, the increase of sinus fat volume was significant in the placebo subgroup (Δ% = 6.8% ± 12.5%), in contrast to the nonsignificant increase in the liraglutide subgroup (Δ% = 3.0% ± 13.8%, P = 0.444). DATA CONCLUSION: Renal sinus fat accumulation responds differently to glucose regulation, showing a reduction in SA patients in contrast to a persistent accumulation in WE patients. A trend of less accumulation of sinus fat in WE patients receiving liraglutide has been observed. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 4.

Altered high-density lipoprotein composition is associated with risk for complications in type 2 diabetes mellitus in South Asian descendants: A cross-sectional, case-control study on lipoprotein subclass profiling.

BACKGROUND: Composition of high-density lipoproteins (HDL) is emerging as an important determinant in the development of microvascular complications in type 2 diabetes mellitus (T2DM). Dutch South Asian (DSA) individuals with T2DM display an increased risk of microvascular complications compared with Dutch white Caucasian (DwC) individuals with T2DM. In this study, we aimed to investigate whether changes in HDL composition associate with increased microvascular risk in this ethnic group and lead to new lipoprotein biomarkers. MATERIALS AND METHODS: Using 1 H nuclear magnetic resonance spectroscopy and Bruker IVDr Lipoprotein Subclass Analysis (B.I.LISA) software, plasma lipoprotein changes were determined in 51 healthy individuals (30 DwC, 21 DSA) and 92 individuals with T2DM (45 DwC, 47 DSA) in a cross-sectional, case-control study. Differential HDL subfractions were investigated using multinomial logistic regression analyses, adjusting for possible confounders including BMI and diabetes duration. RESULTS: We identified HDL compositional differences between healthy and diabetic individuals in both ethnic groups. Specifically, levels of apolipoprotein A2 and HDL-4 subfractions were lower in DSA compared with DwC with T2DM. Apolipoprotein A2 and HDL-4 subfractions also negatively correlated with waist circumference, waist-to-hip ratio, haemoglobin A1c, glucose levels and disease duration in DSA with T2DM, and associated with increased incidence of microvascular complications. CONCLUSION: While HDL composition differed between controls and T2DM in both ethnic groups, the lower levels of lipid content in the smallest HDL subclass (HDL-4) in DSA with T2DM appeared to be more clinically relevant, with higher odds of having diabetes-related pan-microvascular complications such as retinopathy and neuropathy. These typical differences in HDL could be used as ethnicity-specific T2DM biomarkers.

Differences in Inflammatory Pathways Between Dutch South Asians vs Dutch Europids With Type 2 Diabetes.

CONTEXT: South Asian individuals are more prone to develop type 2 diabetes (T2D) coinciding with earlier complications than Europids. While inflammation plays a central role in the development and progression of T2D, this factor is still underexplored in South Asians. OBJECTIVE: This work aimed to study whether circulating messenger RNA (mRNA) transcripts of immune genes are different between South Asian compared with Europid patients with T2D. METHODS: A secondary analysis was conducted of 2 randomized controlled trials of Dutch South Asian (n = 45; age: 55 ± 10 years, body mass index [BMI]: 29 ± 4 kg/m2) and Dutch Europid (n = 44; age: 60 ± 7 years, BMI: 32 ± 4 kg/m2) patients with T2D. Main outcome measures included mRNA transcripts of 182 immune genes (microfluidic quantitative polymerase chain reaction; Fluidigm Inc) in fasted whole-blood, ingenuity pathway analyses (Qiagen). RESULTS: South Asians, compared to Europids, had higher mRNA levels of B-cell markers (CD19, CD79A, CD79B, CR2, CXCR5, IGHD, MS4A1, PAX5; all fold change > 1.3, false discovery rate [FDR] < 0.008) and interferon (IFN)-signaling genes (CD274, GBP1, GBP2, GBP5, FCGR1A/B/CP, IFI16, IFIT3, IFITM1, IFITM3, TAP1; all FC > 1.2, FDR < 0.05). In South Asians, the IFN signaling pathway was the top canonical pathway (z score 2.6; P < .001) and this was accompanied by higher plasma IFN-γ levels (FC = 1.5, FDR = 0.01). Notably, the ethnic difference in gene expression was larger for women (20/182 [11%]) than men (2/182 [1%]). CONCLUSION: South Asian patients with T2D show a more activated IFN-signaling pathway compared to Europid patients with T2D, which is more pronounced in women than men. We speculate that a more activated IFN-signaling pathway may contribute to the more rapid progression of T2D in South Asian compared with Europid individuals.

Renal sinus fat volume in type 2 diabetes mellitus is associated with glycated hemoglobin and metabolic risk factors.

AIMS: We aimed to compare renal sinus fat volume assessed by MRI between patients with type 2 diabetes and healthy volunteers, and investigate the association between renal sinus fat and metabolic traits. METHODS: In this cross-sectional study, renal sinus fat and parenchyma volumes measured on abdominal MRI were compared between patients and controls using analysis of covariance. Associations of renal parameters with clinical characteristics were analyzed using linear regression analysis. RESULTS: A total of 146 participants were enrolled, consisting of 95 type 2 diabetes patients (57.2±8.8years, 49.5% male) and 51 controls (54.0±9.2years, 43.1% male). Patients with diabetes demonstrated larger sinus fat volumes (15.4±7.5cm3 vs. 10.3±7.1cm3, p<0.001) and sinus fat-parenchyma ratio than controls. In the total population, renal sinus fat was positively associated with HbA1c, abdominal VAT, cholesterol and triglycerides, after adjustment for age, sex, ethnicity and type 2 diabetes. In type 2 diabetes patients, increased sinus fat volume was significantly associated with urinary albumin-to-creatinine ratio. CONCLUSION: Renal sinus fat volume is positively associated with several metabolic risk factors including HbA1c level and urinary albumin-to-creatinine ratio in type 2 diabetes patients, indicating a potential role of renal sinus fat in the development of diabetic nephropathy. Future studies are needed to investigate whether sinus fat volume can serve as an early biomarker for diabetic nephropathy.

Efficacy of liraglutide on glycemic endpoints in people of Western European and South Asian descent with T2DM using multiple daily insulin injections: results of the MAGNA VICTORIA studies.

AIMS: Data on the effect of liraglutide on glycemic endpoints in people with T2DM using multiple daily insulin injections (MDI) are scarce, especially in the context of ethnicity. METHODS: This is a secondary analysis of the placebo-controlled randomized clinical "MAGNA VICTORIA" trials in Western European (WE) and South Asian (SA) people with T2DM. Participants had inadequate glycemic control despite using metformin and/or sulfonylurea derivatives and/or insulin. Participants were assigned to liraglutide (1.8 mg) or placebo for 6 months, in addition to standard care. The primary endpoint number of participants reaching target HbA1c was compared for liraglutide versus placebo in the complete dataset and MDI-treated participants using Chi-square test. Liraglutide's efficacy in WE and SA was compared using a generalized linear model. RESULTS: Forty-five subjects were randomized to liraglutide and 51 to placebo. In each group, one participant did not complete the study. Liraglutide-treated patients reached target HbA1c more frequently: 23/45 (51%) vs 11/51 (22%), relative probability 2.4 (1.3-4.3), p = 0.002. Subgroup analysis in 43 MDI participants showed that the proportion reaching target HbA1c using liraglutide was significantly higher than in placebo: 9/22 (41%) vs 1/21 (5%), p = 0.005. There was no difference between WE and SA in terms of liraglutide efficacy (p = 0.18). CONCLUSIONS: Liraglutide treatment resulted in increased chance of reaching target HbA1c as compared to placebo. Liraglutide efficacy was sustained in participants using MDI regimens and those of SA descent. Liraglutide should be considered for T2DM people with inadequate glycemic control despite MDI.

The Effect of Glycemic Control on Renal Triglyceride Content Assessed by Proton Spectroscopy in Patients With Type 2 Diabetes Mellitus: A Single-Center Parallel-Group Trial.

OBJECTIVE: Ectopic lipid accumulation in the kidney (fatty kidney) is a potential driver of diabetic kidney disease, and tight glycemic control can reduce risk of diabetic nephropathy. We assessed whether glycemic control influences renal triglyceride content (RTGC). Furthermore, we compared glucagon-like peptide-1 receptor agonist liraglutide versus standard glucose-lowering therapy. DESIGN AND METHODS: In this single-center parallel-group trial, patients with type 2 diabetes mellitus were randomized to liraglutide or placebo added to standard care (metformin/sulfonylurea derivative/insulin). Changes in RTGC after 26 weeks of glycemic control measured by proton spectroscopy and difference in RTGC between treatment groups were analyzed. RESULTS: Fifty patients with type 2 diabetes mellitus were included in the baseline analysis (mean age, 56.5 ± 9.1 years; range, 33-73 years; 46% males). Seventeen patients had baseline and follow-up measurements. Mean glycated hemoglobin was 7.8 ± 0.8%, which changed to 7.3 ± 0.9% after 26 weeks of glycemic control irrespective of treatment group (P = .046). Log-transformed RTGC was -0.68 ± 0.30% and changed to -0.83 ± 0.32% after 26 weeks of glycemic control irrespective of treatment group (P = .049). A 26-week-to-̶baseline RTGC ratio (95% confidence interval) was significantly different between liraglutide (-0.30 [-0.50, -0.09]) and placebo added to standard care (-0.003 [-0.34, 0.34]) (P = .04). CONCLUSION: In this exploratory study, we found that 26 weeks of glycemic control resulted in lower RTGC, in particular for liraglutide; however, larger clinical studies are needed to assess whether these changes reflect a true effect of glycemic control on fatty kidney.

Liraglutide decreases energy expenditure and does not affect the fat fraction of supraclavicular brown adipose tissue in patients with type 2 diabetes.

BACKGROUND AND AIMS: Several studies have shown that glucagon-like peptide-1 (GLP-1) analogues can affect resting energy expenditure, and preclinical studies suggest that they may activate brown adipose tissue (BAT). The aim of the present study was to investigate the effect of treatment with liraglutide on energy metabolism and BAT fat fraction in patients with type 2 diabetes. METHODS AND RESULTS: In a 26-week double-blind, placebo-controlled trial, 50 patients with type 2 diabetes were randomized to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after treatment for 4, 12 and 26 weeks, we assessed resting energy expenditure (REE) by indirect calorimetry. Furthermore, at baseline and after 26 weeks, we determined the fat fraction in the supraclavicular BAT depot using chemical-shift water-fat MRI at 3T. Liraglutide reduced REE after 4 weeks, which persisted after 12 weeks and tended to be present after 26 weeks (week 26 vs baseline: liraglutide -52 ± 128 kcal/day; P = 0.071, placebo +44 ± 144 kcal/day; P = 0.153, between group P = 0.057). Treatment with liraglutide for 26 weeks did not decrease the fat fraction in supraclavicular BAT (-0.4 ± 1.7%; P = 0.447) compared to placebo (-0.4 ± 1.4%; P = 0.420; between group P = 0.911). CONCLUSION: Treatment with liraglutide decreases REE in the first 12 weeks and tends to decrease this after 26 weeks without affecting the fat fraction in the supraclavicular BAT depot. These findings suggest reduction in energy intake rather than an increase in REE to contribute to the liraglutide-induced weight loss. TRIAL REGISTRY NUMBER: NCT01761318.

Effect of Liraglutide on Cardiovascular Function and Myocardial Tissue Characteristics in Type 2 Diabetes Patients of South Asian Descent Living in the Netherlands: A Double-Blind, Randomized, Placebo-Controlled Trial.

BACKGROUND: The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide may be beneficial in the regression of diabetic cardiomyopathy. South Asian ethnic groups in particular are at risk of developing type 2 diabetes. PURPOSE: To assess the effects of liraglutide on left ventricular (LV) diastolic and systolic function in South Asian type 2 diabetes patients. STUDY TYPE: Prospective, double-blind, randomized, placebo-controlled trial. POPULATION: Forty-seven type 2 diabetes patients of South Asian ancestry living in the Netherlands, with or without ischemic heart disease, who were randomly assigned to 26-week treatment with liraglutide (1.8 mg/day) or placebo. FIELD STRENGTH/SEQUENCE: 3T (balanced steady-state free precession cine MRI, 2D and 4D velocity-encoded MRI, 1 H-MRS, T1 mapping). ASSESSMENT: Primary endpoints were changes in LV diastolic function (early deceleration peak [Edec], ratio of early and late peak filling rate [E/A], estimated LV filling pressure [E/Ea]) and LV systolic function (ejection fraction). Secondary endpoints were changes in aortic stiffness (aortic pulse wave velocity [PWV]), myocardial steatosis (myocardial triglyceride content), and diffuse fibrosis (extracellular volume [ECV]). STATISTICAL TESTS: Data were analyzed according to intention-to-treat. Between-group differences were reported as mean (95% confidence interval [CI]) and were assessed using analysis of covariance (ANCOVA). RESULTS: Liraglutide (n = 22) compared with placebo (n = 25) did not change Edec (+0.2 mL/s2 × 10-3 (-0.3;0.6)), E/A (-0.09 (-0.23;0.05)), E/Ea (+0.1 (-1.2;1.3)) and ejection fraction (0% (-3;2)), but decreased stroke volume (-9 mL (-14;-5)) and increased heart rate (+10 bpm (4;15)). Aortic PWV (+0.5 m/s (-0.6;1.6)), myocardial triglyceride content (+0.21% (-0.09;0.51)), and ECV (-0.2% (-1.4;1.0)) were unaltered. DATA CONCLUSION: Liraglutide did not affect LV diastolic and systolic function, aortic stiffness, myocardial triglyceride content, or extracellular volume in Dutch South Asian type 2 diabetes patients with or without coronary artery disease. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2020;51:1679-1688.

Placebo-controlled randomised trial with liraglutide on magnetic resonance endpoints in individuals with type 2 diabetes: a pre-specified secondary study on ectopic fat accumulation.

AIMS/HYPOTHESIS: The aim of this work was to assess the effect of liraglutide on ectopic fat accumulation in individuals with type 2 diabetes mellitus. METHODS: This study is a pre-specified subanalysis of the MAGNetic resonance Assessment of VICTOza efficacy in the Regression of cardiovascular dysfunction In type 2 diAbetes mellitus (MAGNA VICTORIA) study, with primary endpoints being the effects of liraglutide on left ventricular diastolic and systolic function. The MAGNA VICTORIA study was a single-centre, parallel-group trial in 50 individuals with type 2 diabetes mellitus (BMI >25 kg/m2) who were randomly assigned (1:1, stratified for sex and insulin use) to receive liraglutide 1.8 mg once daily or placebo for 26 weeks, added to standard care. Participants, study personnel and outcome assessors were blinded to treatment allocation. The secondary endpoints of visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT) and epicardial fat were measured with MRI. Hepatic triacylglycerol content (HTGC) and myocardial triacylglycerol content (MTGC) were quantified with proton MR spectroscopy. Between-group differences (change from baseline) were tested for significance using ANCOVA. Mean differences with 95% CIs were reported. RESULTS: The trial was completed in 2016. Twenty-four participants were randomised to receive liraglutide and 26 to receive placebo. One patient in the liraglutide group withdrew consent before having received the study drug and was not included in the intention-to-treat analysis. Liraglutide (n = 23) vs placebo (n = 26) significantly reduced body weight (liraglutide 98.4 ± 13.8 kg to 94.3 ± 14.9 kg; placebo 94.5 ± 13.1 kg to 93.9 ± 13.2 kg; estimated treatment effect -4.5 [95% CI -6.4, -2.6] kg). HbA1c declined in both groups without a significant treatment effect of liraglutide vs placebo (liraglutide 66.7 ± 11.5 mmol/mol to 55.0 ± 13.2 mmol/mol [8.4 ± 1.1% to 7.3 ± 1.2%]; placebo 64.7 ± 10.2 mmol/mol to 56.9 ± 6.9 mmol/mol [8.2 ± 1.0% to 7.5 ± 0.7%]; estimated treatment effect -2.9 [95% CI -8.1, 2.3] mmol/mol or -0.3 [95% CI -0.8, 0.2]%). VAT did not change significantly between groups (liraglutide 207 ± 87 cm2 to 203 ± 88 cm2; placebo 204 ± 63 cm2 to 200 ± 55 cm2; estimated treatment effect -7 [95% CI -24, 10] cm2), while SAT was reduced by a significantly greater extent with liraglutide than with placebo (liraglutide 361 ± 142 cm2 to 339 ± 131 cm2; placebo 329 ± 107 cm2 to 333 ± 125 cm2; estimated treatment effect -29 [95% CI -51, -8] cm2). Epicardial fat did not change significantly between groups (liraglutide 8.9 ± 4.3 cm2 to 9.1 ± 4.7 cm2; placebo 9.6 ± 4.1 cm2 to 9.6 ± 4.6 cm2; estimated treatment effect 0.2 [95% CI -1.5, 1.8] cm2). Change in HTGC was not different between groups (liraglutide 18.1 ± 11.2% to 12.0 ± 7.7%; placebo 18.4 ± 9.4% to 14.7 ± 10.0%; estimated treatment effect -2.1 [95% CI -5.3, 1.0]%). MTGC was not different after treatment with liraglutide (1.5 ± 0.6% to 1.2 ± 0.6%) vs placebo (1.3 ± 0.5% to 1.2 ± 0.6%), with an estimated treatment effect of -0.1 (95% CI -0.4, 0.2)%. There were no adjudicated serious adverse events. CONCLUSIONS/INTERPRETATION: Compared with placebo, liraglutide-treated participants lost significantly more body weight. Liraglutide primarily reduced subcutaneous fat but not visceral, hepatic, myocardial or epicardial fat. Future larger studies are needed to confirm the results of this secondary endpoint study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01761318. FUNDING: This study was funded by Novo Nordisk A/S (Bagsvaerd, Denmark).

Phenotyping diabetic cardiomyopathy in Europeans and South Asians.

BACKGROUND: The pathogenesis and cardiovascular impact of type 2 diabetes (T2D) may be different in South Asians compared with other ethnic groups. The phenotypic characterization of diabetic cardiomyopathy remains debated and little is known regarding differences in T2D-related cardiovascular remodeling across ethnicities. We aimed to characterize the differences in left ventricular (LV) diastolic and systolic function, LV structure, myocardial tissue characteristics and aortic stiffness between T2D patients and controls and to assess the differences in T2D-related cardiovascular remodeling between South Asians and Europeans. METHODS: T2D patients and controls of South Asian and European descent underwent 3 Tesla cardiovascular magnetic resonance imaging (CMR) and cardiac proton-magnetic resonance spectroscopy (1H-MRS). Differences in cardiovascular parameters between T2D patients and controls were examined using ANCOVA and were reported as mean (95% CI). Ethnic group comparisons in the association of T2D with cardiovascular remodeling were made by adding the interaction term between ethnicity and diabetes status to the model. RESULTS: A total of 131 individuals were included (54 South Asians [50.1 ± 8.7 years, 33% men, 33 patients vs. 21 controls) and 77 Europeans (58.8 ± 7.0 years, 56% men, 48 patients vs. 29 controls)]. The ratio of the transmitral early and late peak filling rate (E/A) was lower in T2D patients compared with controls, in South Asians [- 0.20 (- 0.36; - 0.03), P = 0.021] and Europeans [- 0.20 (- 0.36; - 0.04), P = 0.017], whereas global longitudinal strain and aortic pulse wave velocity were similar. South Asian T2D patients had a higher LV mass [+ 22 g (15; 30), P < 0.001] (P for interaction by ethnicity = 0.005) with a lower extracellular volume fraction [- 1.9% (- 3.4; - 0.4), P = 0.013] (P for interaction = 0.114), whilst European T2D patients had a higher myocardial triglyceride content [+ 0.59% (0.35; 0.84), P = 0.001] (P for interaction = 0.002) than their control group. CONCLUSIONS: Diabetic cardiomyopathy was characterized by impaired LV diastolic function in South Asians and Europeans. Increased LV mass was solely observed among South Asian T2D patients, whereas differences in myocardial triglyceride content between T2D patients and controls were only present in the European cohort. The diabetic cardiomyopathy phenotype may differ between subsets of T2D patients, for example across ethnicities, and tailored strategies for T2D management may be required.

Correction to: Effect of liraglutide on cardiac function in patients with type 2 diabetes mellitus: randomized placebo-controlled trial.

Following publication of the original article [1], the authors reported an error in Fig. 3. The bars in the upper right panel that represent heart rate in placebo treated patients is not correct.

A double-blind, placebo-controlled, randomised trial to assess the effect of liraglutide on ectopic fat accumulation in South Asian type 2 diabetes patients.

BACKGROUND: South Asians have a high risk to develop type 2 diabetes, which may be related to substantial ectopic fat deposition. Since glucagon-like peptide-1 analogues can reduce ectopic fat accumulation, the aim of the present study was to assess the effect of treatment with liraglutide for 26 weeks on ectopic fat deposition and HbA1c in South Asian patients with type 2 diabetes. METHODS: In a placebo-controlled trial, 47 South Asian patients with type 2 diabetes were randomly assigned to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after 26 weeks of treatment we assessed abdominal subcutaneous, visceral, epicardial and paracardial adipose tissue volume using MRI. Furthermore, myocardial and hepatic triglyceride content were examined with proton magnetic resonance spectroscopy. RESULTS: In the intention-to-treat analysis, liraglutide decreased body weight compared to placebo (- 3.9 ± 3.6 kg vs - 0.6 ± 2.2 kg; mean change from baseline (liraglutide vs placebo): - 3.5 kg; 95% CI [- 5.3, - 1.8]) without significant effects on the different adipose tissue compartments. HbA1c was decreased in both groups without between group differences. In the per-protocol analysis, liraglutide did decrease visceral adipose tissue volume compared to placebo (- 23 ± 27 cm2 vs - 2 ± 17 cm2; mean change from baseline (liraglutide vs placebo): - 17 cm2; 95% CI [- 32, - 3]). Furthermore, HbA1c was decreased by liraglutide compared to placebo (- 1.0 ± 0.8% (- 10.5 ± 9.1 mmol/mol)) vs (- 0.6 ± 0.8% (- 6.1 ± 8.8 mmol/mol)), with a between group difference (mean change from baseline (liraglutide vs placebo): - 0.6% (- 6.5 mmol/mol); 95% CI [- 1.1, - 0.1 (- 11.5, - 1.5)]). Interestingly, the decrease of visceral adipose tissue volume was associated with the reduction of HbA1c (ß: 0.165 mmol/mol (0.015%) per 1 cm2 decrease of visceral adipose tissue volume; 95% CI [0.062, 0.267 (0.006, 0.024%)]). CONCLUSIONS: While the intention-to-treat analysis did not show effects of liraglutide on ectopic fat and HbA1c, per-protocol analysis showed that liraglutide decreases visceral adipose tissue volume, which was associated with improved glycaemic control in South Asians. Trial registration NCT02660047 (clinicaltrials.gov). Registered 21 January 2016.

Hepatic triglyceride content does not affect circulating CETP: lessons from a liraglutide intervention trial and a population-based cohort.

Cholesteryl ester transfer protein (CETP) is mainly expressed by Kupffer cells in the liver. A reduction of hepatic triglyceride content (HTGC) by pioglitazone or caloric restriction is accompanied by a decrease in circulating CETP. Since GLP-1 analogues also reduce HTGC, we assessed whether liraglutide decreases CETP. Furthermore, we investigated the association between HTGC and CETP in a population-based cohort. In a placebo-controlled trial, 50 patients with type 2 diabetes were randomly assigned to treatment with liraglutide or placebo added to standard care. In this trial and in 1,611 participants of the Netherlands Epidemiology of Obesity (NEO) study, we measured HTGC and circulating CETP by proton magnetic resonance spectroscopy and ELISA, respectively. The HTGC was decreased in the liraglutide group (-6.3%; 95%CI of difference [-9.5, -3.0]) but also in the placebo group (-4.0%; 95%CI[-6.0, -2.0]), without between-group differences. CETP was not decreased by liraglutide (-0.05 µg/mL; 95%CI[-0.13, 0.04]) or placebo (-0.04 µg/mL; 95%CI[-0.12, 0.04]). No association was present between HTGC and CETP at baseline (ß: 0.002 µg/mL per %TG, 95%CI[-0.005, 0.009]) and between the changes after treatment with liraglutide (ß: 0.003 µg/mL per %TG, 95%CI[-0.010, 0.017]) or placebo (ß: 0.006 µg/mL per %TG, 95%CI[-0.012,0.024]). Also, in the cohort n o association between HTGC and CETP was present (ß: -0.001 µg/mL per SD TG, 95%CI[-0.005, 0.003]). A reduction of HTGC after treatment with liraglutide or placebo does not decrease circulating CETP. Also, no association between HTGC and CETP was present in a large cohort. These findings indicate that circulating CETP is not determined by HTGC.Clinical Trial Registration: Clinicaltrials.gov (NCT01761318).

Effect of liraglutide on cardiac function in patients with type 2 diabetes mellitus: randomized placebo-controlled trial.

BACKGROUND: Liraglutide is an antidiabetic agent with cardioprotective effect. The purpose of this study is to test efficacy of liraglutide to improve diabetic cardiomyopathy in patients with diabetes mellitus type 2 (DM2) without cardiovascular disease. METHODS: Patients with DM2 were randomly assigned to receive liraglutide 1.8 mg/day or placebo in this double-blind trial of 26 weeks. Primary outcome measures were LV diastolic function (early (E) and late (A) transmitral peak flow rate, E/A ratio, early deceleration peak (Edec), early peak mitral annular septal tissue velocity (Ea) and estimated LV filling pressure (E/Ea), and systolic function (stroke volume, ejection fraction, cardiac output, cardiac index and peak ejection rate) assessed with CMR. Intention-to-treat analysis of between-group differences was performed using ANCOVA. Mean estimated treatment differences (95% confidence intervals) are reported. RESULTS: 23 patients were randomized to liraglutide and 26 to placebo. As compared with placebo, liraglutide significantly reduced E (- 56 mL/s (- 91 to - 21)), E/A ratio (- 0.17 (- 0.27 to - 0.06)), Edec (- 0.9 mL/s2 * 10-3 (- 1.3 to - 0.2)) and E/Ea (- 1.8 (- 3.0 to - 0.6)), without affecting A (3 mL/s (- 35 to 41)) and Ea (0.4 cm/s (- 0.9 to 1.4)). Liraglutide reduced stroke volume (- 9 mL (- 16 to - 2)) and ejection fraction (- 3% (- 6 to - 0.1)), but did not change cardiac output (- 0.4 L/min (- 0.9 to 0.2)), cardiac index (- 0.1 L/min/m2 (- 0.4 to 0.1)) and peak ejection rate (- 46 mL/s (- 95 to 3)). CONCLUSIONS: Liraglutide reduced early LV diastolic filling and LV filling pressure, thereby unloading the left ventricle. LV systolic function reduced and remained within normal range. Future studies are needed to investigate if liraglutide-induced left ventricular unloading slows progression of diabetic cardiomyopathy into symptomatic stages. Trial registration ClinicalTrials.gov: NCT01761318.

High spatial resolution free-breathing 3D late gadolinium enhancement cardiac magnetic resonance imaging in ischaemic and non-ischaemic cardiomyopathy: quantitative assessment of scar mass and image quality.

PURPOSE: To compare breath-hold (BH) with navigated free-breathing (FB) 3D late gadolinium enhancement cardiac MRI (LGE-CMR) MATERIALS AND METHODS: Fifty-one patients were retrospectively included (34 ischaemic cardiomyopathy, 14 non-ischaemic cardiomyopathy, three discarded). BH and FB 3D phase sensitive inversion recovery sequences were performed at 3T. FB datasets were reformatted into normal resolution (FB-NR, 1.46x1.46x10mm) and high resolution (FB-HR, isotropic 0.91-mm voxels). Scar mass, scar edge sharpness (SES), SNR and CNR were compared using paired-samples t-test, Pearson correlation and Bland-Altman analysis. RESULTS: Scar mass was similar in BH and FB-NR (mean ± SD: 15.5±18.0 g vs. 15.5±16.9 g, p=0.997), with good correlation (r=0.953), and no bias (mean difference ± SD: 0.00±5.47 g). FB-NR significantly overestimated scar mass compared with FB-HR (15.5±16.9 g vs 14.4±15.6 g; p=0.007). FB-NR and FB-HR correlated well (r=0.988), but Bland-Altman demonstrated systematic bias (1.15±2.84 g). SES was similar in BH and FB-NR (p=0.947), but significantly higher in FB-HR than FB-NR (p<0.01). SNR and CNR were lower in BH than FB-NR (p<0.01), and lower in FB-HR than FB-NR (p<0.01). CONCLUSION: Navigated free-breathing 3D LGE-CMR allows reliable scar mass quantification comparable to breath-hold. During free-breathing, spatial resolution can be increased resulting in improved sharpness and reduced scar mass. KEY POINTS: • Navigated free-breathing 3D late gadolinium enhancement is reliable for myocardial scar quantification. • High-resolution 3D late gadolinium enhancement increases scar sharpness • Ischaemic and non-ischaemic cardiomyopathy patients can be imaged using free-breathing LGE CMR.

Cushing's Syndrome and Hypothalamic-Pituitary-Adrenal Axis Hyperactivity in Chronic Central Serous Chorioretinopathy.

OBJECTIVE: Central serous chorioretinopathy (CSC), a specific form of macular degeneration, has been reported as presenting manifestation of Cushing's syndrome. Furthermore, CSC has been associated with both exogenous hypercortisolism and endogenous Cushing's syndrome. It is important to know whether CSC patients should be screened for Cushing's syndrome. Although hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in CSC has been suggested, no detailed evaluation of the HPA axis has been performed in a large cohort of CSC patients. This study aimed to investigate whether Cushing's syndrome prevalence is increased among chronic CSC (cCSC) patients and whether detailed endocrinological phenotyping indicates hyperactivity of the HPA axis. DESIGN: Cross-sectional study. PATIENTS: 86 cCSC patients and 24 controls. MEASUREMENTS: Prevalence of Cushing's syndrome, HPA axis activity. RESULTS: None of the cCSC patients met the clinical or biochemical criteria of Cushing's syndrome. However, compared to controls, HPA axis activity was increased in cCSC patients, reflected by higher 24 h urinary free cortisol, and accompanying higher waist circumference and diastolic blood pressure, whereas circadian cortisol rhythm and feedback were not different. Chronic CSC patients did not report more stress or stress-related problems on questionnaires. CONCLUSION: No case of Cushing's syndrome was revealed in a large cohort of cCSC patients. Therefore, we advise against screening for Cushing's syndrome in CSC patients, unless additional clinical features are present. However, our results indicate that cCSC is associated with hyperactivity of the HPA axis, albeit not accompanied with perception of more psychosocial stress.

1 H-MRS for the assessment of renal triglyceride content in humans at 3T: A primer and reproducibility study.

BACKGROUND: Renal steatosis (fatty kidney) is a potential biomarker for obesity-related renal disease; however, noninvasive assessment of renal fat content remains a technical challenge. PURPOSE: To evaluate reproducibility and explore clinical application of renal metabolic imaging for the quantification of renal triglyceride content (TG) using proton magnetic resonance spectroscopy (1 H-MRS). STUDY TYPE: Reproducibility and clinical cohort study. POPULATION: Twenty-three healthy volunteers (mean age 30.1 ± 13.4 years) and 15 patients with type 2 diabetes mellitus (T2DM) (mean age 59.3 ± 7.0 years). FIELD STRENGTH/SEQUENCE: 3T, single-voxel point resolved spectroscopy (PRESS). ASSESSMENT: Intra- and interexamination reproducibility of renal TG was assessed in healthy volunteers, and compared to T2DM patients. Intraexamination differences were obtained by repeating the 1 H-MRS measurement directly after the first 1 H-MRS without repositioning of the subject or changing surface coil and measurement volumes. Interexamination variability was studied by repeating the scan protocol after removal and replacement of the subject in the magnet, and subsequent repositioning of body coil and measurement volumes. STATISTICAL TESTS: Reproducibility was determined using Pearson's correlation and Bland-Altman analyses. Differences in TG% between healthy volunteers and T2DM patients were assessed using the Mann-Whitney U-test. RESULTS: After logarithmic (log) transformation, both intraexamination (r = 0.91, n = 19) and interexamination (r = 0.73, n = 9) measurements of renal TG content were highly correlated with the first renal TG measurements. Intraexamination and interexamination limits of agreement of renal log TG% were respectively [-1.36%, + 0.84%] and [-0.77%, + 0.62%]. Backtransformed limits of agreement were [-0.89%,+0.57%] and [-0.55%, + 0.43%] multiplied by mean TG for intra- and interexamination measurements. Overall median renal TG content was 0.12% [0.08, 0.22; 25th percentile, 75th percentile] in healthy volunteers and 0.20% [0.13, 0.22] in T2DM patients (P = 0.08). DATA CONCLUSION: Renal metabolic imaging using 3T 1 H-MRS is a reproducible technique for the assessment of renal triglyceride content. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2018;48:507-513.

Parameter optimization for reproducible cardiac 1 H-MR spectroscopy at 3 Tesla.

PURPOSE: To optimize data acquisition parameters in cardiac proton MR spectroscopy, and to evaluate the intra- and intersession variability in myocardial triglyceride content. MATERIALS AND METHODS: Data acquisition parameters at 3 Tesla (T) were optimized and reproducibility measured using, in total, 49 healthy subjects. The signal-to-noise-ratio (SNR) and the variance in metabolite amplitude between averages were measured for: (i) global versus local power optimization; (ii) static magnetic field (B0 ) shimming performed during free-breathing or within breathholds; (iii) post R-wave peak measurement times between 50 and 900 ms; (iv) without respiratory compensation, with breathholds and with navigator triggering; and (v) frequency selective excitation, Chemical Shift Selective (CHESS) and Multiply Optimized Insensitive Suppression Train (MOIST) water suppression techniques. Using the optimized parameters intra- and intersession myocardial triglyceride content reproducibility was measured. Two cardiac proton spectra were acquired with the same parameters and compared (intrasession reproducibility) after which the subject was removed from the scanner and placed back in the scanner and a third spectrum was acquired which was compared with the first measurement (intersession reproducibility). RESULTS: Local power optimization increased SNR on average by 22% compared with global power optimization (P = 0.0002). The average linewidth was not significantly different for pencil beam B0 shimming using free-breathing or breathholds (19.1 Hz versus 17.5 Hz; P = 0.15). The highest signal stability occurred at a cardiac trigger delay around 240 ms. The mean amplitude variation was significantly lower for breathholds versus free-breathing (P = 0.03) and for navigator triggering versus free-breathing (P = 0.03) as well as for navigator triggering versus breathhold (P = 0.02). The mean residual water signal using CHESS (1.1%, P = 0.01) or MOIST (0.7%, P = 0.01) water suppression was significantly lower than using frequency selective excitation water suppression (7.0%). Using the optimized parameters an intrasession limits of agreement of the myocardial triglyceride content of -0.11% to +0.04%, and an intersession of -0.15% to +0.9%, were achieved. The coefficient of variation was 5% for the intrasession reproducibility and 6.5% for the intersession reproducibility. CONCLUSION: Using approaches designed to optimize SNR and minimize the variation in inter-average signal intensities and frequencies/phases, a protocol was developed to perform cardiac MR spectroscopy on a clinical 3T system with high reproducibility. J. Magn. Reson. Imaging 2016;44:1151-1158.