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Effects of Exenatide on Cardiac Function, Perfusion, and Energetics

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Effects of Exenatide on Cardiac Function, Perfusion, and Energetics Chen et al. Cardiovasc Diabetol (2017) 16:67 DOI 10.1186/s12933-017-0549-z Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Efects of exenatide on cardiac function, perfusion, and energetics in type 2 diabetic patients with cardiomyopathy: a randomized controlled trial against insulin glargine Weena J. Y. Chen1*, Michaela Diamant1^, Karin de Boer2, Hendrik J. Harms3, Lourens F. H. J. Robbers2, Albert C. van Rossum2, Mark H. H. Kramer1, Adriaan A. Lammertsma3 and Paul Knaapen2 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, efects 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 fow reserve 15 (P < 0.01), measured by ­[ O]H2O positron emission tomography (PET), were impaired in T2DM patients as compared to healthy controls. Myocardial oxygen consumption and myocardial efciency, measured using ­[11C]acetate PET and CMR derived stroke volume, were not diferent 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 efciency as compared to healthy controls. Exenatide or insulin glargine had no efects on cardiac function, perfusion or oxidative metabolism. Trial registration NCT00766857 Keywords: Diabetes mellitus type 2, Exenatide, Cardiac function, Myocardial perfusion, Myocardial oxidative metabolism Background Te optimal bloodglucose-lowering therapy in T2DM Type 2 diabetes mellitus (T2DM) is associated with an patients and HF is still under debate. Multiple agents increased risk of heart failure (HF), even after adjusting [2–4] have been linked to cardiovascular events. Other for coronary artery disease (CAD) and hypertension [1]. agents [5, 6] have been associated with a lower risk of cardiovascular events. *Correspondence: [email protected] Preliminary studies have shown recovery of left ven- ^ Deceased tricular (LV) function during glucagon-like peptide-1 1 Diabetes Center/Department of Internal Medicine, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands (GLP-1) administration in HF patients irrespective of the Full list of author information is available at the end of the article diabetic status [7, 8]. However, underlying mechanisms © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chen et al. Cardiovasc Diabetol (2017) 16:67 Page 2 of 12 for this efect remain to be elucidated. Small scaled breakfast and study medication, prior to randomization, studies suggested enhanced endothelial function and and patients underwent follow-up measurements after increased perfusion by GLP-1 [9, 10]. Moreover, shift 26 weeks of treatment. towards augmented glucose metabolism has favora- ble efects on cardiac energetics [11]. Both phenomena Outcomes have important prognostic relevance [12, 13]. At pre- Te primary outcome in the current study was efects on sent, efects of GLP-1 receptor agonists (RA) on myocar- LVEF after 26-week treatment of exenatide versus insulin dial perfusion and energetics in T2DM patients with LV glargine in T2DM patients with LV systolic dysfunction. systolic dysfunction are unclear. In view of the diabetes Secondary outcomes were diferences in myocardial per- pandemic and the associated high risk of HF, bloodglu- fusion and energetics in T2DM patients with LV systolic cose-lowering agents that can be prescribed safely are of dysfunction versus healthy BMI-matched healthy con- great importance. Terefore, the aim of this study was to trols, and efects on myocardial perfusion and energetics examine efects of GLP-1RA on cardiac function, myo- after 26-week treatment of exenatide versus insulin glar- cardial perfusion, and energetics in T2DM patients with gine in T2DM patients with LV systolic dysfunction. LV systolic dysfunction compared to insulin glargine. CMR Methods Measurements were performed using a 1.5 Tesla whole- Participants body magnetic resonance imaging (MRI) scanner (MAG- T2DM patients with LV dysfunction, LV ejection frac- NETOM Avanto, Siemens, Erlangen, Germany). All tion (LVEF) < 50% [as documented in the medical images were acquired with electrocardiographic trig- records, measured using echocardiogram, radionuclide gering, during repeated expiration breath-holds. Cine angiogram or cardiovascular magnetic resonance imag- imaging was used to measure LV dimensions and sys- ing (CMR)], above 18 years, body mass index (BMI) of tolic function. After localizing scout scans, cine images 25–40 kg m−2, hemoglobin A1C (HbA1c) of 6.5–10.0% were acquired using a retrospectively triggered, balanced (48–86 mmol mol−1), were randomized, at an alloca- steady-state free precession (SSFP) gradient echo sequence tion ratio of 1:1, open-label, to exenatide or insulin in three long axis views (2-, 3-, and 4-chamber views). Sub- glargine on top of ongoing use of oral glucose-lowering sequently, short axis images (slice thickness 5 mm, gap agents (metformin or metformin and sulfonylurea) after 5 mm), covering the whole LV from mitral valve annulus a run-in period of 10 weeks. Exclusion criteria were to apex, was acquired. Delayed contrast enhancement renal or liver impairment, malignancy, cardiovascular (DCE) imaging was used to quantify myocardial scarring. events <3 months, insulin, thiazolidinediones, incretin- DCE images were acquired 15–20 min after intravenous based therapies <4 months and chronic glucocorticoid administration of 0.2 mmol kg−1 gadolinium-based con- use. Patients with contraindication for positron emis- trast agent (gadoterate meglumine, Dotarem®, Guerbet, sion tomography (PET) or CMR (e.g. claustrophobia, France). DCE images were acquired in the same short and implanted metal devices, rhythm other than sinus) were long axis views as those used for cine imaging. For this excluded. Healthy BMI-matched subjects with normal purpose, a 2D segmented inversion-recovery prepared glucose metabolism (assessed by 75-g oral glucose-toler- gradient echocardiography sequence was applied. ance test) served as controls. All participants gave writ- ten informed consent. Te study protocol was approved CMR data analysis by the Medical Ethics Review committee of the VU Uni- LVEF and global LV parameters were quantifed using versity Medical Center, and was performed in full com- MASS software package (MEDIS, Leiden, Te Nether- pliance with the declaration of Helsinki. lands). Endocardial and epicardial borders were outlined manually in end-diastolic and end-systolic frames of all Study procedures short-axis slices. Presence, and degree of fbrosis, of total 5 µg exenatide twice daily was injected subcutaneously, ventricular mass, were quantifed from DCE images 15 min before breakfast and dinner, for 4 weeks, followed using the 5-standard deviation method [15]. by an increase to 10 µg twice daily. Insulin glargine was initiated at 10 IU once daily, injected subcutaneously PET according to normal standard dosages. Patients were PET assessments were performed using a hybrid PET/ instructed to increase the dose based on fasting blood computed tomography (CT) scanner (Gemini TF-64, glucose levels (<5.6 mmol L−1) according to a prespeci- Philips Healthcare, Best, Te Netherlands). Oxidative fed treat-to-target algorithm [14]. CMR and PET were metabolism was measured using [11C]acetate and perfu- 15 performed in the morning within 4 h after a standardized sion using [ O]H2O. Chen et al. Cardiovasc Diabetol (2017) 16:67 Page 3 of 12 [11C]acetate PET scan Data analysis After a survey scan to position the patient, 370 MBq of Rate pressure product (RPP) was obtained by multiply- [11C]acetate was injected intravenously (5 mL bolus, infu- ing systolic BP (SBP) with heart rate (HR). Resting MBF sion speed 0.8 mL s−1) followed by a saline fush (35 mL, corrected for RPP was derived as MBF at rest divided infusion speed 2 mL s−1). Simultaneously, an emission by RPP at rest, multiplied by 10 4. Coronary fow reserve scan was started, acquiring list mode
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