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A protocol for a randomised, double-blind, placebo-controlled study of the effect of LIraglutide on left VEntricular function in chronic heart failure patients with and without type 2 diabetes (The LIVE Study).

ABSTRACT: Heart failure is one of the most common cardiovascular complications of diabetes and the most disabling and deadly complication too. Many antidiabetic agents have been associated with increased morbidity and mortality in a subset of patients with chronic heart failure (CHF); thus, new treatment modalities are warranted. Interestingly, a beneficial effect of the incretin hormone, GLP-1, on cardiac function has been suggested in patients with diabetes and patients without diabetes. Liraglutide (Victoza) is a GLP-1 analogue developed for the treatment of type 2 diabetes (T2D); however, its impact on cardiac function has not previously been investigated in patients with CHF. This prompted us to investigate whether liraglutide treatment for 24?weeks improves left ventricular ejection fraction (LVEF) in patients with CHF with and without T2D compared with placebo treatment.An investigator-initiated, multicentre, randomised, double-blind, parallel, placebo-controlled intervention trial. In total, 240 patients with CHF (with and without T2D) with LVEF?45% will be randomised to either subcutaneous injection of liraglutide 1.8?mg or matching placebo once daily for 24?weeks. The effect of liraglutide on left ventricular function will be evaluated by advanced echocardiography, including three-dimensional contrast echocardiography.The study will be performed and monitored according to the Good Clinical Practice-International Conference on Harmonisation (GCP-ICH) regulations and conducted according to the principles of the Helsinki Declaration. The Danish Medicines Agency, the local Research Ethics Committee and the Danish Data Protection Agency have approved the study.ClinicalTrials.gov Identifier: NCT01472640.

SUBMITTER: Jorsal A

PROVIDER: S-EPMC4039804 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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A protocol for a randomised, double-blind, placebo-controlled study of the effect of LIraglutide on left VEntricular function in chronic heart failure patients with and without type 2 diabetes (The LIVE Study).

Jorsal Anders A Wiggers Henrik H Holmager Pernille P Nilsson Brian B Nielsen Roni R Boesgaard Trine Welløv TW Kumme Anja A Møller Jacob Eifer JE Videbæk Lars L Kistorp Caroline C Gustafsson Ida I Tarnow Lise L Flyvbjerg Allan A

BMJ open 20140520 5

<h4>Introduction</h4>Heart failure is one of the most common cardiovascular complications of diabetes and the most disabling and deadly complication too. Many antidiabetic agents have been associated with increased morbidity and mortality in a subset of patients with chronic heart failure (CHF); thus, new treatment modalities are warranted. Interestingly, a beneficial effect of the incretin hormone, GLP-1, on cardiac function has been suggested in patients with diabetes and patients without diab ...[more]

PMID: 24844271

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Project description:This study tested whether cardiac sympathetic innervation assessed by metaiodobenzylguanidine (MIBG) activity has long-term prognostic value in combination with left ventricular hypertrophy (LVH) and left atrial size in heart failure (HF) patients without reduced left ventricular ejection fraction (LVEF).A single-centre prospective cohort study.With primary endpoints of cardiac death and rehospitalisation due to HF progression, 178 consecutive symptomatic HF patients with 74% men, mean age of 56 years and mean LVEF of 64.5% were followed up for 80 months. The entry criteria consisted of LVEF more than 50%, completion of predischarge clinical evaluations including cardiac MIBG and echocardiographic studies and at least more than 1-year follow-up when survived.Thirty-four patients with cardiac evens had larger left atrial dimension (LAD), increased LV mass index, reduced MIBG activity quantified as heart-to-mediastinum ratio (HMR) than did the others. Multivariable Cox analysis showed that LAD and HMR were significant predictors (HR of 1.080 (95% CI 1.00 to 1.16, p=0.044) and 0.107 (95% CI 0.01 to 0.61, p=0.012, respectively). Thresholds of HMR (1.65) and LAD (37 mm) were closely related to identification of high-risk patients. In particular, HMR was a significant determinant of cardiac events in both patients with and without LV hypertrophy. Reduced HMR with enlarged LAD or LV hypertrophy identified patients at most increased risk; overall log-rank value, 11.5, p=0.0032 for LAD and 17.5, p=0.0002, respectively.In HF patients without reduced LV ejection fraction, impairment of cardiac sympathetic innervation is related to cardiac outcomes independently and synergistically with LA size and LV hypertrophy. Cardiac sympathetic innervation assessment can contribute to better risk-stratification in combination with evaluation of LA size and LV mass but is needed to be evaluated for establishing aetiology-based risk assessment in HF patients at increased risk.

Project description:BackgroundGlucagon-like peptide-1 receptor (GLP-1R) activation may improve myocardial performance in the context of ischaemia, independent of glycaemic control, in individuals with and without type 2 diabetes mellitus.MethodsThe LIONESS trial was a single-centre randomised double-blind placebo-controlled crossover study to determine whether prolonged GLP-1R activation could improve exercise haemodynamics in chronic stable angina patients. Eligibility criteria comprised angiographic evidence of obstructive coronary artery disease (CAD) and an abnormal baseline exercise tolerance test (ETT) demonstrating?>?0.1 mV of planar or downsloping ST-segment depression (STD). Those randomised to active agent started with a 1-week run-in phase of 0.6 mg liraglutide daily, an established injectable GLP-1R agonist, followed by 1 week of 1.2 mg liraglutide, after which patients performed a week 2 ETT. Patients then self-administered 1.8 mg liraglutide for a week before completing a week 3 ETT. The placebo arm received visually and temporally matched daily saline injections. Participants then crossed over to a 3-week course of saline injections interspersed with a week 5 ETT and week 6 ETT and vice versa. Co-primary endpoints were rate pressure product (RPP) at 0.1 mV STD and magnitude of STD at peak exercise.ResultsTwenty-two patients (21 without diabetes) were randomised. There was no significant difference between saline versus liraglutide in the co-primary endpoints of RPP achieved at 0.1 mV STD (saline vs. liraglutide 1.2 mg p?=?0.097; saline vs. liraglutide 1.8 mg p?=?0.48) or the degree of STD at peak exercise (saline vs. liraglutide 1.2 mg p?=?0.68; saline vs. liraglutide 1.8 mg p?=?0.57). Liraglutide did not cause symptomatic hypoglycaemia, renal dysfunction, acute pancreatitis or provoke early withdrawal from the trial. Liraglutide significantly reduced weight (baseline 88.75?±?16.5 kg vs. after liraglutide 87.78?±?16.9 kg; p?=?0.0008) and improved the lipid profile (mean total cholesterol: at baseline 3.97?±?0.88 vs. after liraglutide 3.56?±?0.71 mmol/L; p?<?0.0001).ConclusionLiraglutide did not enhance exercise tolerance or haemodynamics compared with saline placebo during serial treadmill testing in patients with established obstructive CAD. It did, however, significantly reduce weight and improve the lipid profile. Trial Registration ClinicalTrials.gov Identifier NCT02315001. Retrospectively registered on 11th December 2014.

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Dataset Information

A protocol for a randomised, double-blind, placebo-controlled study of the effect of LIraglutide on left VEntricular function in chronic heart failure patients with and without type 2 diabetes (The LIVE Study).

Publications

A protocol for a randomised, double-blind, placebo-controlled study of the effect of LIraglutide on left VEntricular function in chronic heart failure patients with and without type 2 diabetes (The LIVE Study).

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