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Table 1 Evidence for GLP-1-mediated cardioprotection in humans

From: Design and rationale for the randomised, double-blinded, placebo-controlled Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) crossover study

Author and year published Pathologic substrate Agent Control Hypothesis/Question Pertinent findings Potential Limitations
Nikolaidis et al. 2004 [37] Myocardial ischaemia/reperfusion injury GLP-1 (N=10) Standard therapy post PPCI (N=11) Can a 72-hour infusion of GLP-1 improve global and regional LV function for post infarct myocardial dysfunction following successful PPCI? • GLP-1 therapy improved global LVEF (p<0.01) • Small, single-centre, nonrandomized pilot study
• GLP-1 improved regional (p<0.001) and global (p<0.001) WMSI • Truncated 4-day follow-up window does not allow for extrapolation of results
• Improvements seen in diabetics and non-diabetics and after anterior and non-anterior MI
• GLP-1 reduced hospital stay significantly (p<0.02)
Sokos et al. 2006 [38] Dilated Cardiomyopathy GLP-1 (n=12) Maximum standard therapy (n=9) Can a 5-week subcutaneous infusion of GLP-1 improve both LVEF and functional capacity? • LVEF improved significantly in the GLP-1 arm ((p<0.001) and was unchanged in the control arm • Small, single-centre, open-label, nonrandomised study
• Type I diabetics excluded but not Type II – potential source of confounding and increased incidence of hypoglycaemia
• 6MWT distance improved significantly in the GLP-1 arm (p<0.001)
• Quality of life improved significantly with GLP-1 (p<0.001) • No mention of exact infusion volume – essential in a heart failure cohort
• Functional improvements seen in diabetics and non-diabetics
Sokos et al. 2007 [39] CABG surgery GLP-1 (n=12) Standard therapy (n=12) Can peri- and postoperative GLP-1 administration improve haemodynamic recovery after CABG surgery? • No difference in LVEF or cardiac index between the groups • Small numbers despite randomisation
• Control group required greater use of inotropic and vasoactive infusions • Hypothesis-generating
• More frequent arrhythmias seen in control group
Halbirk et al. 2010 [40] Ischaemic cardiomyopathy GLP-1 (n=10 crossover) Saline (n=10 crossover) GLP-1 can improve cardiac function and exercise capacity in non-diabetic patients with heart failure. • Cardiac index and LVEF remained unchanged • Small, single-centre study
• BNP levels remained unchanged • Active intervention with a 48-hour GLP-1 infusion may have been too short to mediate any improvement in cardiovascular indices
• Hypoglycaemic events related to GLP-1 treatment were seen in 8 patients
• Trial protocol only completed in 75% of patients
Read et al. 2010 [41] Myocardial ischaemia (mediated by dobutamine stress) Sitagliptin (n=14 crossover) Placebo (n=14 crossover) Increased availability of endogenous GLP-1 through DPP-4 inhibition will protect the heart against postischaemic LV dysfunction. • Greater increase in myocardial performance after sitagliptin at peak stress (p=0.0001) • Small study sample
• Myocardial stunning seen in controls after dobutamine stress whereas sitagliptin maintained LV function • Hypothesis-generating
• Sitagliptin had a greater beneficial effect on ischaemic vs. nonischaemic LV segments
Read et al. 2011 [42] Myocardial ischaemia/reperfusion injury GLP-1 (n=10) Saline (n=10) Can GLP-1 protect the heart against ischaemic dysfunction associated with serial 1-minute coronary balloon occlusions during PCI and mitigate myocardial stunning? • GLP-1 infusion improved recovery of LV systolic and diastolic function at 30 minutes post 1-minute coronary balloon occlusion compared with control (p=0.02) • Study too small to assess any clinical endpoints
• Coronary flow not assessed
• GLP-1 infusion reduced LV dysfunction after a second 1-minute coronary balloon occlusion compared with control (p=0.01) • Hypothesis-generating
Read et al. 2012 [43] Myocardial ischaemia (mediated by dobutamine stress) GLP-1 (n=14 crossover) Saline (n=14 crossover) Can GLP-1 protect the heart from ischaemic LV dysfunction and improve myocardial response to dobutamine stress? • Greater increase in LVEF at peak stress during GLP-1 infusion • Small study sample
• No myocardial stunning seen during GLP-1 infusion • Study not powered to examine clinical end points
• GLP-1 improved myocardial performance specifically in LV segments subtended by a stenosed vessel and did not in segments receiving an unobstructed blood supply
Lønborg et al. 2012 [44] Myocardial I/R injury Exenatide (n=85) Saline (n=87) Can exenatide protect against reperfusion injury in STEMI patients following PPCI? • Significantly greater myocardial salvage index in the exenatide group (p=0.003) post PPCI • LVEF after 90 days was not significantly different between the two groups
• Patients in the exenatide group developed significantly smaller infarcts for an equivalent area at risk (p=0.011) • Study cohort too small to detect a difference in 30-day clinical events
McCormick et al. 2014 [45] Myocardial ischaemia (mediated by dobutamine stress) Sitagliptin (taken for 4 weeks) (n=19) Standard oral hypoglycaemic agents (n=19) Can chronic DPP-4 inhibition with sitagliptin protect the heart from ischaemic LV dysfunction and improve myocardial response to demand ischaemia during dobutamine stress in Type 2 diabetes patients with CAD • No difference in the rate pressure products at baseline, peak stress, or recovery between the sitagliptin and control scans • Small study sample
• Cannot exclude degree of variation in individual response to dobutamine during 2 consecutive stress echocardiograms separated by a number of weeks
• At peak stress there was a greater increase in global ejection fraction following sitagliptin therapy (p<0.0001)
• At peak stress sitagliptin enhanced regional LV function – seen predominantly in ischaemic segments (p=0.001) whereas there was no effect in non-ischaemic segments (p=0.87) • CAD defined by the presence of a single proximal stenosis >50% in at least 1 epicardial coronary artery – some might argue this level of obstruction would not be haemodynamically significant
  1. Key: GLP-1 = glucagon-like peptide-1; PPCI = primary percutaneous coronary intervention; LVEF = left ventricular ejection fraction; 6MWT = 6-minute walk test; WMSI = wall motion score index; BNP = brain natriuretic peptide; CABG = coronary artery bypass grafting; STEMI = ST-elevation myocardial infarction; PCI = percutaneous coronary intervention; DPP-4 = dipeptidyl dipeptidase-4; CAD = coronary artery disease.