BackgroundEthnic 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... Show moreBackgroundEthnic 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.PurposeTo 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 TypeRetrospective.PopulationNinety-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/Sequence3.0 T dual-echo fast gradient-echo pulse sequence using two-point Dixon technique with a phase-correction algorithm.AssessmentChanges 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 TestsNormality 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.ResultsRenal sinus fat decreased in SA patients (Delta% = -7.6% +/- 14.8%), but increased in WE patients (Delta% = 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 (Delta% = 6.8% +/- 12.5%), in contrast to the nonsignificant increase in the liraglutide subgroup (Delta% = 3.0% +/- 13.8%, P = 0.444).Data ConclusionRenal 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 Level4Technical EfficacyStage 4 Show less
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... Show moreObjective: 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 andMethods: 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. (C) 2020 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. Show less
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... Show moreAims 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 +/- 8.8 years, 49.5% male) and 51 controls (54.0 +/- 9.2 years, 43.1% male). Patients with diabetes demonstrated larger sinus fat volumes (15.4 +/- 7.5 cm(3) vs. 10.3 +/- 7.1 cm(3), 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. Show less
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... Show moreAims 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. Show less
Background and aims: The separate cardiovascular effects of type 2 diabetes and adiposity remain to be examined. This study aimed to investigate the role of insulin resistance in the relations of... Show moreBackground and aims: The separate cardiovascular effects of type 2 diabetes and adiposity remain to be examined. This study aimed to investigate the role of insulin resistance in the relations of visceral (VAT), abdominal subcutaneous (aSAT) adipose tissue and total body fat (TBF) to cardiovascular remodeling.Methods and results: In this cross-sectional analysis of the population-based Netherlands Epidemiology of Obesity study, 914 middle-aged individuals (46% men) were included. Participants underwent magnetic resonance imaging. Standardized linear regression coefficients (95%CI) were calculated, adjusted for potential confounding factors. All fat depots and insulin resistance (HOMA-IR), separate from VAT and TBF, were associated with lower mitral early and late peak filling rate ratios (E/A): -0.04 (-0.09;0.01) per SD (54 cm(2)) VAT; -0.05 (-0.10;0.00) per SD (94 cm(2)) aSAT; -0.09 (-0.16;-0.02) per SD (8%) TBF; -0.11 (-0.17;-0.05) per 10-fold increase in HOMA-IR, whereas VAT and TBF were differently associated with left ventricular (LV) end-diastolic volume: -8.9 (-11.7;-6.1) mL per SD VAT; +5.4 (1.1;9.7) mL per SD TBF. After adding HOMA- IR to the model to evaluate the mediating role of insulin resistance, change in E/A was -0.02 (-0.07;0.04) per SD VAT; -0.03 (-0.08;0.02) per SD aSAT; -0.06 (- 0.13;0.01) per SD TBF, and change in LV end-diastolic volume was -7.0 (-9.7;-4.3) mL per SD VAT. In women, adiposity but not HOMA-IR was related to higher aortic arch pulse wave velocity.Conclusion: Insulin resistance was associated with reduced diastolic function, separately from VAT and TBF, and partly mediated the associations between adiposity depots and lower diastolic function. (C) 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved. Show less
Over the past decades, the number of individuals with type 2 diabetes has been growing worldwide. Type 2 diabetes is a major health concern, as it is related to several conditions, including heart... Show moreOver the past decades, the number of individuals with type 2 diabetes has been growing worldwide. Type 2 diabetes is a major health concern, as it is related to several conditions, including heart failure and coronary artery disease. Despite remarkable advances in cardiovascular prevention and treatment, heart disease remains a common cause of death and an important contributor to health loss. The aim of this thesis was to characterize cardiovascular remodeling associated with metabolic disturbances, using a variety of magnetic resonance techniques. This thesis demonstrates that reduced diastolic function is a common characteristic of myocardial remodeling in type 2 diabetes and obesity, but also a potential marker for the detection of patients at increased cardiovascular risk after hematopoietic stem cell transplantation and possibly a contributing factor in the pathogenesis of ventricular arrhythmia after myocardial infarction. Also, in this thesis, it was shown that the evaluation of visceral adiposity and myocardial triglyceride content may help to identify distinct cardiometabolic phenotypes and to better understand the cardiometabolic actions of the glucagon-like peptide 1 receptor agonist liraglutide. With the emergence of non-contrast cardiovascular protocols, magnetic resonance techniques may be increasingly used for cardiometabolic phenotyping in population-based cohorts as well as clinical studies. Show less
Background and aims: Several studies have shown that glucagon-like peptide-1 (GLP1) analogues can affect resting energy expenditure, and preclinical studies suggest that they may activate brown... Show moreBackground and aims: Several studies have shown that glucagon-like peptide-1 (GLP1) 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. (C) 2020 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved. Show less
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... Show moreBackground 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, H-1-MRS, T-1 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/s(2) x 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. Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2019. Show less
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... Show moreAims/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/m(2)) 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). HbA(1c) 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 cm(2) to 203 +/- 88 cm(2); placebo 204 +/- 63 cm(2) to 200 +/- 55 cm(2); estimated treatment effect -7 [95% CI -24, 10] cm(2)), while SAT was reduced by a significantly greater extent with liraglutide than with placebo (liraglutide 361 +/- 142 cm(2) to 339 +/- 131 cm(2); placebo 329 +/- 107 cm(2) to 333 +/- 125 cm(2); estimated treatment effect -29 [95% CI -51, -8] cm(2)). Epicardial fat did not change significantly between groups (liraglutide 8.9 +/- 4.3 cm(2) to 9.1 +/- 4.7 cm(2); placebo 9.6 +/- 4.1 cm(2) to 9.6 +/- 4.6 cm(2); estimated treatment effect 0.2 [95% CI -1.5, 1.8] cm(2)). 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. Funding This study was funded by Novo Nordisk A/S (Bagsvaerd, Denmark). Show less
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... Show moreBackground 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 (H-1-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. Show less
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.
BackgroundLiraglutide 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... Show moreBackgroundLiraglutide 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.MethodsPatients with DM2 were randomly assigned to receive liraglutide 1.8mg/day or placebo in this double-blind trial of 26weeks. 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.Results23 patients were randomized to liraglutide and 26 to placebo. As compared with placebo, liraglutide significantly reduced E (-56mL/s (-91 to -21)), E/A ratio (-0.17 (-0.27 to -0.06)), Edec (-0.9mL/s(2)*10(-3) (-1.3 to -0.2)) and E/Ea (-1.8 (-3.0 to -0.6)), without affecting A (3mL/s (-35 to 41)) and Ea (0.4cm/s (-0.9 to 1.4)). Liraglutide reduced stroke volume (-9mL (-16 to -2)) and ejection fraction (-3% (-6 to -0.1)), but did not change cardiac output (-0.4L/min (-0.9 to 0.2)), cardiac index (-0.1L/min/m(2) (-0.4 to 0.1)) and peak ejection rate (-46mL/s (-95 to 3)).ConclusionsLiraglutide 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. Show less
