Dataset Information

Design of a randomised controlled trial of the effects of empagliflozin on myocardial perfusion, function and metabolism in type 2 diabetes patients at high cardiovascular risk (the SIMPLE trial).

ABSTRACT: INTRODUCTION:A diagnosis of type 2 diabetes (T2D) more than doubles the risk of cardiovascular disease (CVD), with heart failure (HF) being one of the most common complications with a severe prognosis. The landmark Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Paitients (EMPA-REG OUTCOME) study demonstrated that treatment with the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin rapidly and significantly reduces CVD mortality and admission rates for HF. However, the mechanisms behind this reduction in clinical events are unknown.This study was designed to investigate the effects of the SGLT-2 inhibitor empagliflozin on myocardial perfusion and function in patients with T2D and high CVD risk. METHODS AND ANALYSIS:In this investigator-initiated, randomised, double-blind controlled clinical trial, 92 patients with T2D and established CVD or high CVD risk will be randomised to treatment with empagliflozin 25?mg or a matching placebo for 13 weeks. The primary outcome measure is change in myocardial flow reserve measured quantitatively by Rubidium-82 position emission tomography. In a substudy, invasive haemodynamics at rest and during exercise will be measured at baseline and following the intervention, using right heart catheterisation. ETHICS AND DISSEMINATION:The study protocol (v7, 02/08/2018) has been approved by the Ethics Committee of the Capital Region, Danish Data Protection Board and the Danish Medicines Agency, and it will be monitored according to the Good Clinical Practice regulations from the International Conference on Harmonization. The results be submitted to international peer-reviewed journals and be presented at conferences. The data will be made available to the public via EudraCT and www.clinicaltrials.gov. TRIAL REGISTRATION NUMBER:NCT03151343.

SUBMITTER: Jurgens M

PROVIDER: S-EPMC6887087 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Design of a randomised controlled trial of the effects of empagliflozin on myocardial perfusion, function and metabolism in type 2 diabetes patients at high cardiovascular risk (the SIMPLE trial).

Jürgens Mikkel M Schou Morten M Hasbak Philip P Kjær Andreas A Wolsk Emil E Zerahn Bo B Wiberg Mikkel M Brandt Niels Høgh NH Gæde Peter Haulund PH Rossing Peter P Faber Jens J Inzucchi Silvio S Gustafsson Finn F Kistorp Caroline Michaela CM

BMJ open 20191127 11

<h4>Introduction</h4>A diagnosis of type 2 diabetes (T2D) more than doubles the risk of cardiovascular disease (CVD), with heart failure (HF) being one of the most common complications with a severe prognosis. The landmark Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Paitients (EMPA-REG OUTCOME) study demonstrated that treatment with the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin rapidly and significantly reduces CVD mortality and admission ra ...[more]

PMID: 31780586

Similar Datasets

Project description:IntroductionSodium-glucose co-transporter-2 (SGLT-2) inhibitors have been shown to have beneficial effects on various cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) in primary prevention and in those with a high CV risk profile. However, the mechanism(s) responsible for these CV benefits remain elusive and unexplained. The aim of the DAPAHEART study will be to demonstrate that treatment with SGLT-2 inhibitors is associated with greater myocardial insulin sensitivity in patients with T2D, and to determine whether this improvement can be attributed to a decrease in whole-body (and tissue-specific) insulin resistance and to increased myocardial perfusion and/or glucose uptake. We will also determine whether there is an appreciable degree of improvement in myocardial-wall conditions subtended by affected and non-affected coronary vessels, and if this relates to changes in left ventricular function.MethodsThe DAPAHEART trial will be a phase III, single-center, randomized, two-arm, parallel-group, double-blind, placebo-controlled study. A cohort of 52 T2D patients with stable coronary artery disease (without any previous history of myocardial infarction, with or without previous percutaneous coronary intervention), with suboptimal glycemic control (glycated hemoglobin [HbA1c] 7-8.5%) on their current standard of care anti-hyperglycemic regimen, will be randomized in a 1:1 ratio to dapagliflozin or placebo. The primary outcome is to detect changes in myocardial glucose uptake from baseline to 4 weeks after treatment initiation. The main secondary outcome will be changes in myocardial blood flow, as measured by 13N-ammonia positron emission tomography/computed tomography (PET/CT). Other outcomes include cardiac function, glucose uptake in skeletal muscle, adipose tissue, liver, brain and kidney, as assessed by fluorodeoxyglucose (FDG) PET-CT imaging during hyperinsulinemic-euglycemic clamp; pericardial, subcutaneous and visceral fat, and browning as observed on CT images during FDG PET-CT studies; systemic insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp, glycemic control, urinary glucose output; and microbiota modification.DiscussionSGLT-2 inhibitors, in addition to their insulin-independent plasma glucose-lowering effect, are able to directly (substrate availability, fuel utilization, insulin sensitivity) as well as indirectly (cardiac after-load reduction, decreased risk factors for heart failure) affect myocardial functions. Our study will provide novel insights into how these drugs exert CV protection in a diabetic population.Trial registrationEudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.

Project description:BackgroundMyocardial perfusion cardiovascular magnetic resonance (CMR) is a well-established method for detection of ischemic heart disease. However, ECG gating problems can result in image degradation and non-diagnostic scans, particularly in patients with arrhythmias.MethodsA turboFLASH saturation recovery pulse sequence was used without any ECG triggering. One saturation pulse followed by 4-5 slices of undersampled radial k-space images was acquired rapidly, on the order of 40-50 msec per image. The acquisition of the set of 4-5 slices was continuously repeated approximately 4 times per second. An iterative constrained reconstruction method was used to reconstruct the ungated images. The ungated perfusion images were post-processed into three different sets of images (ungated, self-gated to near systole, and self-gated to near diastole). To test the ungated approach and compare the different processing methods, 8 patients scheduled for coronary angiography underwent stress and rest perfusion imaging with the ungated acquisition. Six patients had a history of atrial fibrillation (AF). Three blinded readers assessed image quality and presence/absence of disease.ResultsAll 8 subjects successfully completed the perfusion CMR protocol and 7/8 underwent coronary angiography. Three patients were in atrial fibrillation during CMR. Overall, the CMR images were of high quality as assessed by the three readers. There was little difference in image quality between patients in AF compared to those in sinus rhythm (3.6±0.7 vs. 3.3±0.5). Stress/rest perfusion imaging showed normal perfusion in 4 patients, fixed perfusion defects in 2 patients, and reversible perfusion defects in 2 patients, corresponding with angiographic results. Pooled results from the independent readers gave a sensitivity of 0.92 (CI 0.65-0.99) and specificity of 0.92 (CI 0.65-0.99) for the detection of coronary artery disease using ungated perfusion imaging. The same sensitivity, and a specificity of 1 (CI 0.76-1), was achieved when the images were self-gated after acquisition into near systole or near diastole.ConclusionsUngated radial dynamic perfusion CMR can give high quality imaging in patients in sinus rhythm and during atrial fibrillation. In this small cohort, high diagnostic accuracy was possible with this rapid perfusion imaging sequence. An ungated approach simplifies the acquisition and could expand the role of perfusion CMR to include patients with arrhythmia and those with gating problems.

Project description:Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME™ trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes.Patients who were drug-naïve (HbA1c ?7.0% and ?9.0%), or on background glucose-lowering therapy (HbA1c ?7.0% and ?10.0%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until ?691 confirmed primary outcome events have occurred, providing a power of 90% to yield an upper limit of the adjusted 95% CI for a hazard ratio of <1.3 with a one-sided ? of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved.Between Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41% from Europe, 20% from North America, and 19% from Asia). At baseline, the mean age was 63?±?9 years, BMI 30.6?±?5.3 kg/m2, HbA1c 8.1?±?0.8%, and eGFR 74?±?21 ml/min/1.73 m2. The study is expected to report in 2015.EMPA-REG OUTCOME™ will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection.Clinicaltrials.gov NCT01131676.

Project description:AimsAlthough the reno-protective effects of sodium-glucose cotransporter 2 inhibitors are known in patients with heart failure or type 2 diabetes mellitus (T2DM), this effect has not been confirmed in patients with acute myocardial infarction (AMI).Methods and resultsThe prospective, multicentre, randomized, double-blind, placebo-controlled EMBODY trial investigated patients with AMI and T2DM in Japan. The eligible patients included adults aged 20 years or older, diagnosed with AMI and T2DM, and who could be discharged within 2-12 weeks after the onset of AMI. One hundred and five patients were randomized (1:1) to receive once daily 10 mg empagliflozin or placebo within 2 weeks of AMI onset. In this sub-analysis, we investigated the time course of renal functional parameters such as serum creatinine levels and estimated glomerular filtration rate (eGFR) from baseline to Weeks 4, 12, and 24. Ninety-six patients (64 ± 11 years, 78 male) were included in the full analysis (n = 46 and 50 in the empagliflozin and placebo groups, respectively). We used serum creatinine and eGFR as indicators of renal function. In the placebo group, eGFR decreased from 66.14 mL/min/1.73 m2 at baseline to 62.77 mL/min/1.73 m2 by Week 24 (P = 0.023) but remained unchanged in the empagliflozin group (from 64.60 to 64.36 mL/min/1.73 m2 , P = 0.843). In the latter group, uric acid improved from 5.8 mg/dL at baseline to 4.9 mg/dL at Week 24 (P < 0.001). In the earlier analysis of 56 patients with eGFR ≥ 60 mL/min/1.73 m2 , the eGFR decreased and the serum creatinine increased from baseline to 24 weeks in the placebo group, significantly different to the empagliflozin group (-6.61 vs. +0.22 mL/min/1.73 m2 , P = 0.008 and +0.063 vs. -0.001 mg/dL, P = 0.030, respectively). The changes in serum creatinine and eGFR from baseline to Week 24 were significantly correlated with those in uric acid in the placebo group (r = 0.664, P < 0.001 and r = -0.675, P < 0.001, respectively) but not in the empagliflozin group.ConclusionsEmpagliflozin prevented the kidney functional decline in patients with AMI and T2DM, especially those with baseline eGFR ≥ 60 mL/min/1.73 m2 . Early administration of sodium-glucose cotransporter 2 inhibitors in these patients is considered desirable for renal protection.

Dataset Information

Design of a randomised controlled trial of the effects of empagliflozin on myocardial perfusion, function and metabolism in type 2 diabetes patients at high cardiovascular risk (the SIMPLE trial).

Publications

Design of a randomised controlled trial of the effects of empagliflozin on myocardial perfusion, function and metabolism in type 2 diabetes patients at high cardiovascular risk (the SIMPLE trial).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets