Effect of additional treatment with EXenatide in patients with an Acute Myocardial Infarction (EXAMI): study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Myocardial infarction causes irreversible loss of cardiomyocytes and may lead to loss of ventricular function, morbidity and mortality. Infarct size is a major prognostic factor and reduction of infarct size has therefore been an important objective of strategies to improve outcomes. In experimental studies, glucagon-like peptide 1 and exenatide, a long acting glucagon-like peptide 1 receptor agonist, a novel drug introduced for the treatment of type 2 diabetes, reduced infarct size after myocardial infarction by activating pro-survival pathways and by increasing metabolic efficiency.</p> <p>Methods</p> <p>The EXAMI trial is a multi-center, prospective, randomized, placebo controlled trial, designed to evaluate clinical outcome of exenatide infusion on top of standard treatment, in patients with an acute myocardial infarction, successfully treated with primary percutaneous coronary intervention. A total of 108 patients will be randomized to exenatide (5 μg bolus in 30 minutes followed by continuous infusion of 20 μg/24 h for 72 h) or placebo treatment. The primary end point of the study is myocardial infarct size (measured using magnetic resonance imaging with delayed enhancement at 4 months) as a percentage of the area at risk (measured using T2 weighted images at 3-7 days).</p> <p>Discussion</p> <p>If the current study demonstrates cardioprotective effects, exenatide may constitute a novel therapeutic option to reduce infarct size and preserve cardiac function in adjunction to reperfusion therapy in patients with acute myocardial infarction.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01254123">NCT01254123</a></p

Endocriene bijwerkingen van checkpointremmers

Checkpoint inhibition has emerged as a promising therapeutic strategy for several types of cancer. Immune-related adverse effects (irAEs) commonly involve the endocrine system. Distinguishing endocrine side effect-related symptoms from disease progression or treatment-related toxicity can be challenging. If not recognized in time, endocrine irAEs may be life-threatening. As the use of checkpoint inhibitors is expected to increase, there is a need for more awareness of endocrine irAEs amongst health care professionals. We describe three cases that illustrate the importance of timely recognition, patient education and the management of endocrinopathies. Two patients who were treated with the checkpoint inhibitor ipilimumab developed hypophysitis and subsequent episodes of hypocortisolism. These cases underline both the frequency of diagnostic delay and the importance of patient education with regard to glucocorticoid stress dosage. The third patient presented with diabetes mellitus after administration of nivolumab. A multidisciplinary approach is warranted to ensure optimal care for patients with endocrine irAEs

Effects of exenatide on cardiac function, perfusion, and energetics in type 2 diabetic patients with cardiomyopathy: a randomized controlled trial against insulin glargine

Abstract Background Multiple bloodglucose-lowering agents have been linked to cardiovascular events. Preliminary studies showed improvement in left ventricular (LV) function during glucagon-like peptide-1 receptor agonist administration. Underlying mechanisms, however, are unclear. The purpose of this study was to investigate myocardial perfusion and oxidative metabolism in type 2 diabetic (T2DM) patients with LV systolic dysfunction as compared to healthy controls. Furthermore, effects of 26-weeks of exenatide versus insulin glargine administration on cardiac function, perfusion and oxidative metabolism in T2DM patients with LV dysfunction were explored. Methods and results Twenty-six T2DM patients with LV systolic dysfunction (cardiac magnetic resonance (CMR) derived LV ejection fraction (LVEF) of 47 ± 13%) and 10 controls (LVEF of 59 ± 4%, P < 0.01 as compared to patients) were analyzed. Both myocardial perfusion during adenosine-induced hyperemia (P < 0.01), and coronary flow reserve (P < 0.01), measured by [15O]H2O positron emission tomography (PET), were impaired in T2DM patients as compared to healthy controls. Myocardial oxygen consumption and myocardial efficiency, measured using [11C]acetate PET and CMR derived stroke volume, were not different between the groups. Eleven patients in the exenatide group and 12 patients in the insulin glargine group completed the trial. Systemic metabolic control was improved after both treatments, although, no changes in cardiac function, perfusion and metabolism were seen after exenatide or insulin glargine. Conclusions T2DM patients with LV systolic dysfunction did not have altered myocardial efficiency as compared to healthy controls. Exenatide or insulin glargine had no effects on cardiac function, perfusion or oxidative metabolism. Trial registration NCT0076685

Activin a is associated with impaired myocardial glucose metabolism and left ventricular remodeling in patients with uncomplicated type 2 diabetes

Activin A released from epicardial adipose tissue has been linked to contractile dysfunction and insulin resistance in cardiomyocytes. This study investigated the role of activin A in clinical diabetic cardiomyopathy by assessing whether circulating activin A levels associate with cardiometabolic parameters in men with uncomplicated type 2 diabetes (T2D), and the effects of treatment with pioglitazone versus metformin on these associations. Seventy-eight men with uncomplicated T2D and fourteen healthy men with comparable age were included, in this randomized, double-blind, active comparator intervention study. All T2D men were on glimipiride monotherapy, and randomized to a 24-week intervention with either pioglitazone or metformin. Cardiac dimensions and -function were measured using magnetic resonance imaging, whilst myocardial glucose metabolism (MMRglu) was determined using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography during a hyperinsulinemic-euglycemic clamp. Circulating activin A levels were comparable in T2D men and controls. Activin A levels were independently inversely associated with MMRglu, and positively with left ventricular mass/volume (LVMV)-ratio in T2D men. Intervention with metformin decreased activin A levels, whereas pioglitazone did not alter activin A levels. The changes in plasma activin A levels were not correlated with the changes in MMRglu following either pioglitazone or metformin treatment. A borderline significant correlation (p = 0.051) of changes in plasma activin A levels and changes in LVMV-ratio was observed after pioglitazone treatment. Circulating activin A levels are associated with impaired myocardial glucose metabolism and high LVMV-ratio in patients with uncomplicated T2D, reflecting a potential detrimental role in early human diabetic cardiomyopathy.Trial registration numberCurrent Controlled Trials SRCTN5317748

Cardioprotective Properties of Omentin-1 in Type 2 Diabetes: Evidence from Clinical and In Vitro Studies

Context: Adipokines are linked to the development of cardiovascular dysfunction in type 2 diabetes (DM2). In DM2-patients, circulating levels of omentin-1, an adipokine preferentially expressed in epicardial adipose tissue, are decreased. This study investigated whether omentin-1 has a cardioprotective function. Methods: Omentin-1 levels in plasma and cardiac fat depots were determined in DM2-patients versus controls. Moreover, the relation between omentin-1 levels and cardiac function was examined in men with uncomplicated DM2. Finally, we determined whether omentin-1 could reverse the induction of cardiomyocyte dysfunction by conditioned media derived from epicardial adipose tissue from patients with DM2. Results: Omentin-1 was highly expressed and secreted by epicardial adipose tissue, and reduced in DM2. Circulating omentin-1 levels were lower in DM2 versus controls, and positively correlated with the diastolic parameters early peak filling rate, early deceleration peak and early deceleration mean (all P,0.05). The improved diastolic function followin

Cardioprotective properties of omentin-1 in type 2 diabetes: evidence from clinical and in vitro studies

Contains fulltext : 118105.pdf (publisher's version ) (Open Access)CONTEXT: Adipokines are linked to the development of cardiovascular dysfunction in type 2 diabetes (DM2). In DM2-patients, circulating levels of omentin-1, an adipokine preferentially expressed in epicardial adipose tissue, are decreased. This study investigated whether omentin-1 has a cardioprotective function. METHODS: Omentin-1 levels in plasma and cardiac fat depots were determined in DM2-patients versus controls. Moreover, the relation between omentin-1 levels and cardiac function was examined in men with uncomplicated DM2. Finally, we determined whether omentin-1 could reverse the induction of cardiomyocyte dysfunction by conditioned media derived from epicardial adipose tissue from patients with DM2. RESULTS: Omentin-1 was highly expressed and secreted by epicardial adipose tissue, and reduced in DM2. Circulating omentin-1 levels were lower in DM2 versus controls, and positively correlated with the diastolic parameters early peak filling rate, early deceleration peak and early deceleration mean (all P<0.05). The improved diastolic function following pioglitazone treatment associated with increases in omentin-1 levels (P<0.05). In vitro, exposure of cardiomyocytes to conditioned media derived from epicardial adipose tissue from patients with DM2 induced contractile dysfunction and insulin resistance, which was prevented by the addition of recombinant omentin. CONCLUSION: These data identify omentin-1 as a cardioprotective adipokine, and indicate that decreases in omentin-1 levels could contribute to the induction of cardiovascular dysfunction in DM2

Characteristics of subjects for determination of circulating omentin-1 levels.

<p>Data are mean ± SD or median (interquartile range). <i>P</i>-values for differences between variables were calculated using the students <i>t</i>-test in case of normally distributed data, or the Mann-Whitney U-test in case of non-Gaussian distributions data.</p>***<p>indicates <i>P</i><0.001;</p>**<p><i>P</i><0.01;</p>*<p><i>P</i><0.05;</p>#<p><i>P</i><0.10. A, diastolic atrial contraction; BMI, body mass index; DM2, type 2 diabetes; E, early diastolic filling phase; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LV, left ventricular; MFAE, myocardial fatty acid esterification; MFAO, myocardial fatty acid oxidation; MFAU, myocardial fattu acid uptake; MMRGlu, myocardial metabolic glucose metabolism; M-value, whole body insulin sensitivity.</p>‡<p>adapted from Rijzewijk et al. 2009 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0059697#pone.0059697-Rijzewijk1" target="_blank">[23]</a>.</p

Expression and secretion of omentin-1 in intrathoracal adipose tissue depots.

<p>Representative Western blot (<b>A</b>) and quantification (<b>B</b>) of omentin-1 expression in paired epicardial (EAT), pericardial (PAT), and subcutaneous (SAT) adipose tissue biopsies of patients with (DM2, n = 7) and without (ND, n = 6) type 2 diabetes. Equal loading was verified by probing the immunoblots with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) antibody. (<b>C</b>) Quantification of omentin-1 levels in conditioned media generated from paired EAT, PAT and SAT explants from DM2- and ND-patients. Data are expressed as mean ± SEM (n = 6 patients per group). ***indicates <i>P</i><0.001; **<i>P</i><0.01, *<i>P</i><0.05 for differences between ND and DM2 (ANOVA followed by Bonferonni analysis for multiple comparisons); ^###indicates <i>P</i><0.001; ^##<i>P</i><0.01, and ^#<i>P</i><0.05 for differences between the various fat depots (paired <i>t</i>-test).</p

Correlations between plasma omentin-1 levels and anthropometric, plasma, hemodynamic parameters, and cardiac dimensions and function.

<p>Data are Pearson’s r. In case of non-Gaussian distributions, parameters were ln-transformed for correlation analysis. A, diastolic atrial contraction; BMI, body mass index; DM2, type 2 diabetes; E, early diastolic filling phase; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LV, left ventricular; MFAE, myocardial fatty acid esterification; MFAO, myocardial fatty acid oxidation; MFAU, myocardial fattu acid uptake; MMRGlu, myocardial metabolic glucose metabolism; M-value, whole body insulin sensitivity.</p>#<p><i>P</i><0.10;</p>*<p><i>P</i><0.05;</p>**<p><i>P</i><0.01;</p>***<p><i>P</i><0.001.</p

Plasma omentin-1 levels in men with uncomplicated type 2 diabetes.

<p>Plasma omentin-1 levels, fat distribution, insulin sensitivity and diastolic parameters were determined in healthy control men (n = 14) and men with uncomplicated type 2 diabetes (DM2) (n = 78). (<b>A</b>) Whisker plot (median, min-max) depicting plasma omentin-1 levels in controls and DM2-patients. Differences in circulating omentin-1 levels were analyzed using a Mann-Whitney U-test. **indicates <i>P</i><0.01. Regression analysis identified significant correlations between baseline omentin-1 plasma levels and E peak filling rate (<b>B</b>), early deceleration peak (<b>C</b>), M-value (<b>D</b>), visceral fat volume (<b>E</b>), and systolic blood pressure (<b>F</b>). A straight line indicates a regression line for all subjects. A dashed line indicates a regression line for healthy controls only.</p