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Abstract

Incretin is a gut derived peptide hormone secreted in the intestine after food ingestion, and is degraded rapidly after secretion by dipeptidyl peptidase (DPP)-4. Incretin-based therapy, such as glucagon-like peptide (GLP)-1 and the DPP-4 inhibitor, has been proposed as a new therapeutic approach for the treatment of type 2 diabetic patients. In the past few years, growing evidence also demonstrated the cardioprotective effects of incretin-based therapy, especially during ischaemia-reperfusion (I/R) injury in both the animal models and in clinical studies. However, inconsistent reports exist regarding the use of these pharmacological interventions. In this article, a comprehensive review regarding both basic and clinical studies reporting the effects of GLP-1 and DPP-4 inhibitors on I/R hearts is presented and discussed. The consistent findings as well as controversial results are summarised, focusing on the effects of incretin on the infarct size, left ventricular function and haemodynamic improvement during an I/R injury.

Keywords

Incretin GLP-1 DPP-4 inhibitor ischaemia-reperfusion injury heart

Introduction

Diabetes mellitus (DM) has become a significant health problem in most nations with the number of patients dramatically soaring and expected to reach 366 million by the year 2030.¹ It has been shown that patients with type 2 diabetes mellitus (T2DM) have a two- to four-fold higher risk of coronary disease and stroke mortality.^2–6 Although several new anti-diabetic drugs have been discovered in the past decades, the therapies have been limited by their adverse effects such as weight gain, hypoglycaemia, fluid retention and an unexpected cardiovascular risk.^7–10 Therefore, new anti-diabetic drugs that could control hyperglycaemia and reduce the risk of cardiovascular events are of potential benefit to T2DM patients.

Incretin is a gut derived peptide hormone which enhances endogenous insulin secretion and reduces glucagon secretion, resulting in reduced blood glucose after food consumption.^11–14 Its secretion is greatly influenced by ingestion.¹⁵ The incretin hormone has been classified into glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP)-1. GIP is secreted by the enteroendocrine K cell of the proximal intestine, while GLP-1 is released from the enteroendocrine L cell of the distal intestine. GLP-1 is responsible for the majority of the incretin effect on pancreatic β-cell function. The secretion of GLP-1 is lower in patients with T2DM than normal, suggesting that this hormone contributes to the pathogenesis of the disease.¹⁶

The circulating GLP-1 has two isotypes: GLP-1 (7-36) and GLP-1 (7-37), in which GLP-1 (7-36) is responsible for 80% of active GLP-1.¹⁷ GLP-1 has insulinotropic, insulinomimetic and glucagonostatic effects.¹⁸ GLP-1 binds to GLP-1 receptors (GLP-1Rs) leading to regulatory actions which are an enhancement of β-cell function and proliferation, enhancement of glucose-dependent insulin secretion from β-cell, activation of insulin biosynthesis, suppression of elevated glucagon secretion, suppression of food intake and slowing of gastric emptying.^11,19 However, the therapeutic drawback is that the circulating GLP-1 level decreases rapidly, i.e. less than two minutes, after secretion due to being degraded by dipeptidyl peptidase (DPP)-4 enzymes and renal clearance.^20–23 DPP-4 enzyme degrades GLP-1 (7-36) by removing an N-terminal dipeptide, resulting in its metabolite, GLP-1 (9-36), which has 1000-fold lower affinity to GLP-1Rs.²¹ It has been shown that the inhibition of DPP-4 could enhance the level of intact GLP-1 and prolong its action time.²⁴ Thus, two classes of drugs have been recently used for incretin enhancement in T2DM, including GLP-1 analogues and DPP-4 inhibitors. While GLP-1 analogues (i.e. exenatide, liraglutide and albiglutide) increase the GLP-1 level to a supraphysiological level, DPP-4 inhibitors (i.e. vildagliptin, sitagliptin and saxagliptin) conserve and prolong intact GLP-1 availability within a physiological level.

Although the primary physiological function of GLP-1 is related to the control of plasma glucose, GLP-1Rs have been ubiquitously found in a variety of extra-pancreatic tissues including the central and peripheral nervous system, kidney, lung, gastrointestinal tract, blood vessel and heart both in rodents and humans.^13,25 Since GLP-1Rs in the heart are similar to in the pancreas,²⁵ it has been suggested that drugs targeting incretin enhancement may potentially affect the heart.

DM has been shown to increase cardiovascular risk including increased incidence of myocardial infarction.² With the undesirable effects of several anti-diabetic drugs such as those in the thiazolidinedione group, i.e. rosiglitazone, that increased the cardiovascular morbidity and mortality,^8,9 it is essential that any new anti-diabetic drug be investigated for both beneficial and harmful effects on the cardiovascular system. In this review, reports from basic and clinical studies regarding the effects of GLP-1 and DPP-4 inhibitor on cardiac function and infarct size in an ischaemic-reperfused heart are comprehensively summarised. Key results are critically discussed with emphasis placed on consistent findings. Inconsistent results are also highlighted to more fully explore what is known and what remains to be discovered.

Effects of GLP-1 on the infarct size

GLP-1 has been shown to have an infarct limiting effect in both in vitro and in vivo models of ischaemia-reperfusion (I/R) injury (Table 1). GLP-1 co-administered with DPP-4 inhibitor, valine pyrrolide (VP), could reduce the infarct size ranging from 39% to 58% in isolated Langendorff rat hearts whether given prior to ischaemia or during the reperfusion period.^26–29 However, the administration of GLP-1²⁸ or DPP-4 inhibitor^26–28 alone failed to reduce the infarct size. These studies suggested the synergistic effect of DPP-4 inhibition and exogenous GLP-1 on the infarct limiting effect in which DDP-4 inhibitor enhanced endogenous GLP-1 level and reduced exogenous GLP-1 degradation.

Table 1.

Summary of the beneficial effects of GLP-1 on the infarct size.

Animal species	Study model	Drug/dose/route	Major findings	Interpretation	References
Rabbit	I/R LCX ligation 30-min ischaemia 180-min reperfusion	GLP-1-Tf 10 mg/kg Pretreatment 12 h, SC At reperfusion, IV	1. GLP-1-Tf decreased infarct size in both pretreatment and post-ischaemia by 23% and 25%, respectively. 2. GLP-1-Tf decreased apoptotic index.	GLP-1-Tf decreased infarct size by reducing myocardial apoptosis whether given pretreatment or post-ischaemia.	Matsubara et al.³¹
Normal mice High fat diet with streptozotocin-induced diabetic mice	MI LAD ligation 28-day ischaemia	Liraglutide Pretreatment 75 or 200 µg/kg, IP, twice daily for 7 days 75 µg/kg, IP, twice daily for 7 days	1. Liraglutide at dose 75 and 200 µg/kg increased survival rate in both normal and diabetic mice. 2. Liraglutide at dose 200 µg/kg reduced infarct size by 27% and reduced HW/BW ratio. 3. Liraglutide activated cardioprotective signalling pathway, e.g. pAkt, pGSK3β, PPARβ/δ, nNrf-2, and HO-1 before MI through GLP-1R. 4. Liraglutide increased pAkt, pGSK3β, and decreased caspase 3, ANP and MMP-9 after MI. 5. Liraglutide increased cAMP level and decreased caspase 3 in cardiomyocytes. 6. Concomitant administration of GLP-1R antagonist abolished effects of liraglutide on cardiomyocytes.	Liraglutide decreased infarct size. The mechanism could be due to activation of cardioprotective signalling pathway. e.g. pAkt, pGSK3β, and reduce caspase-3 activation through GLP-1R dependent pathway.	Noyan-Ashraf et al.³⁶
Pig	I/R LCX ligation 75-min ischaemia 3-day reperfusion	Exenatide 10 µg, SC and IV 5 min before reperfusion 10 µg, SC, twice daily during reperfusion	1. Exenatide reduced infarct size by 39%. 2. Exenatide increased Akt and Bcl-2 phosphorylation. 3. Exenatide decreased caspase 3. 4. Exenatide decreased nuclear oxidative stress. 5. Exenatide increased antioxidant enzyme.	Exenatide decreased infarct size by activating pro-survival kinase, Akt and Bcl-2 phosphorylation as well as decreasing pro-apoptotic caspase 3. Exenatide also increased anti-oxidant, resulting in decreased nuclear oxidative stress.	Timmers et al.³³
Rat	I/R LAD ligation 30-min ischaemia 120-min reperfusion	Pretreated with VP 20 mg/kg, SC, 30 min before experiment + infusion with GLP-1 4.8 pmol/kg per min throughout experiment	VP + GLP-1 reduced infarct size by 58%.	DPP-4 inhibitor combined with GLP-1 could reduce infarct size.	Bose et al.²⁶
Rat	I/R LAD ligation 30-min ischaemia 120-min reperfusion	rGLP-1 30 pM/kg per min, infusion beginning at 28 min after occlusion until the end of reperfusion	1. rGLP-1 reduced infarct size by 79%. 2. rGLP-1 attenuated PMN activation. 3. rGLP-1 decreased PMN accumulation in ischaemic myocardium. 4. In vitro, rGLP-1 attenuated PMN activation; this effect was abolished by GLP-1R antagonist.	GLP-1 mitigated I/R injury by reduced infarct size and inhibited PMN-mediated reperfusion injury through GLP-1R dependent pathway.	Dokken et al.⁴¹
Rat	I/R LAD ligation 30-min ischaemia 24-h reperfusion	Albiglutide 1, 3, 10 mg/kg per day, SC, once daily, for 3 days	1. Albiglutide at doses 3 and 10 mg/kg reduced infarct size by 26%. 2. Albiglutide increased cAMP level in ischaemic myocardium. 3. Albiglutide increased myocardial glucose uptake. 4. Albiglutide increased carbohydrate oxidation and reduced fat oxidation.	Infarct limiting effect of albiglutide was associated with improvement of cardiac metabolic efficiency.	Bao et al.³²
Isolated rat heart	I/R Left main coronary artery ligation (regional ischaemia) 35-min ischaemia 120-min reperfusion	VP 20 mg/L + GLP-1 0.3 nM in perfusion buffer, throughout experiment	1. VP + GLP-1 reduced infarct size by 55%. 2. Using GLP-1 inhibitor, cAMP inhibitor, PI3K inhibitor and MAPK inhibitor abolished infarct limiting effect. 3. VP + GLP-1 treated group increased phosphorylated BAD.	Infarct limiting effect of GLP-1 could be due to activation of pro-survival kinase including cAMP, PI3K, MAPK and promote BAD phosphorylation.	Bose et al.²⁶
Isolated rat heart	I/R Left main coronary artery ligation (regional ischaemia) 35-min ischaemia 120-min reperfusion	VP 20 mg/L + GLP-1 0.3 nM in perfusion buffer, throughout experiment	1. GLP-1 + VP reduced infarct size by 50%. 2. Rapamycin, p70s6K inhibitor, abolished infarct limiting effect. 3. GLP-1 + VP did not increase phosphorylated p70s6K.	GLP-1 with DPP-4 inhibitor could reduce infarct size by activation of Akt-p70s6K-BAD pathway.	Bose et al.²⁸
Isolated rat heart	I/R Left main coronary artery ligation (regional ischaemia) 35-min ischaemia 120-min reperfusion	Pretreatment VP 20 mg/L + GLP-1 0.3 nM, 15 min before I/R VP 20 mg/L + GLP-1 0.3 nM, during 15 min of reperfusion	Given VP + GLP-1 before ischaemia or at reperfusion reduced infarct size by 49% and 48%, respectively.	GLP-1 with DPP-4 inhibitor could use as preconditioning or post-conditioning agent to reduce infarct size.	Bose et al.²⁷
Isolated rat heart	I/R 35-min global no flow ischaemia 120-min reperfusion	VP 40 µM + GLP-1 0.3 nM, during 15 min of reperfusion	1. VP + GLP-1 reduced infarct size by 39%. 2. GLP-1 with GLP-1R antagonist could not reduce infarct size.	Infarct limiting effect of GLP-1 was mediated by GLP-1R.	Ossum et al.²⁹
Isolated rat heart	I/R 45-min global no flow ischaemia 120-min reperfusion	Exendin-4 0.03, 0.3, 3.0 nM, during 15 min at reperfusion	1. Exendin-4 at 0.03 and 0.3 nM reduced infarct size by 53% and 56%, respectively. 2. Exendin-4 with GLP-1R antagonist cannot reduce infarct size.	Infarct limiting effect of exendin-4 was mediated by GLP-1R.	Sonne et al.³⁰

I/R: ischaemic-reperfusion, LCX: left circumflex coronary artery; GLP-1-Tf: glucagon-like peptide-1-transferrin, SC: subcutaneous route, IV: intravenous route, MI: myocardial infarction, LAD: left anterior descending coronary artery, IP: intraperitoneal route, HW/BW: heart weight/body weight; GLP-1R: GLP-1 receptor; pAkt: phosphorylated Akt; pGSK: phosphorylated glycogen synthase kinase; PPAR: peroxisome proliferated-activated receptors; HO-1: heme-oxygenase-1; ANP: atrial natriuretic peptide; MMP: matrix metallopeptidase; VP: valine pyrrolide; rGLP-1: recombinant GLP-1; PMN: polymorphonuclear neutrophils; DPP-4: dipeptidyl peptidase-4; PI3K: phosphoinositide 3-kinase; MAPK: mitogen-activated peptide kinase; BAD: Bcl-2 associated death promoter.

Another line of drug that has been used to enhance an incretin effect is a DPP-4 resistant GLP-1R agonist. Exendin-4, a hormone found in the saliva of the Gila monster, at 0.03 and 0.3 nM has been shown to reduce the infarct size, while 3.0 nM exendin-4 could not show this benefit, suggesting a biphasic infarct limiting effect.³⁰ Human transferrin (Tf) was also demonstrated to prolong the GLP-1 action. Administration of GLP-1-Tf could effectively reduce the infarct size in rabbits, given either before or after coronary occlusion.³¹ Recently, albiglutide, another GLP-1 analogue, has been shown to increase cAMP in an ischaemic myocardium and improve cardiac metabolic efficiency by increasing glucose metabolism and reducing fat oxidation, which results in 26% reduction of infarct size.³²

In a pig model, exenatide has been shown to reduce the infarct size,³³ whereas the other two studies with a shorter period of I/R using recombinant GLP-1 (rGLP-1)³⁴ or liraglutide³⁵ could not demonstrate any improvement in infarct size (Table 2). This discrepancy could be due to a different duration and site of occlusion, therapeutic drugs and drug concentrations. This hypothesis is supported by a report by Noyan-Ashraf and colleagues, demonstrating that the optimal time and dose of liraglutide, GLP-1 analogue, played an important role in infarct size reduction, improved survival rate and contractile function in both normoglycaemic and diabetic mice.³⁶

Table 2.

Summary of the neutral effects of GLP-1 on the infarct size.

Animal species	Study model	Drug/dose/route	Major findings	Interpretation	References
Pig	I/R LAD ligation 60-min ischaemia 120-min reperfusion	rGLP-1, 3 pmol/kg per min, 120 min before experiment + rGLP-1, 3 pmol/kg per min, IV perfusion during I/R rGLP-1, 3 pmol/kg per min, IV perfusion during I/R	1. rGLP-1 did not reduce infarct size. 2. rGLP-1 increased plasma insulin level. 3. rGLP-1 lowered blood glucose level. 4. rGLP-1 decreased interstitial levels of pyruvate and lactate.	rGLP-1 did not reduce infarct size, but altered myocardial glucose utilisation, which was associated with insulin level.	Kavianipour et al.³⁴
Pig	I/R Balloon LAD occlusion 40-min ischaemia 150-min reperfusion	Liraglutide Pretreatment 10 µg/kg, SC, once daily for 3 days	1. Liraglutide did not reduce infarct size. 2. VF incidence and time to VF was not different between liraglutide and vehicle.	Liraglutide did not reduce infarct size.	Kristensen et al.³⁵
Isolated rat heart	I/R Left main coronary artery ligation (regional ischaemia) 35-min ischaemia 120-min reperfusion	GLP-1 0.3 nM in perfusion buffer, throughout experiment	GLP-1 alone did not reduce infarct size.	GLP-1 alone could not reduce infarct size. DPP-4 inhibitor was important for exogenous GLP-1 function to reduce infarct size.	Bose et al.²⁸
Isolated rat heart	I/R 35-min global no flow ischaemia 120-min reperfusion	VP 40 µM + GLP-1 (9-36) 0.3 nM, during 15 min of reperfusion	GLP-1 (9-36) + VP did not reduce infarct size.	GLP-1 metabolite with DPP-4 inhibitor did not reduce infarct size.	Ossum et al.²⁹
Isolated rat heart	I/R 45-min global no flow ischaemia 120-min reperfusion	GLP-1 (9-36) 0.03, 0.3, 3.0 nM, during 15 min of reperfusion	GLP-1 (9-36) did not reduce infarct size.	GLP-1 metabolite did not reduce infarct size.	Sonne et al.³⁰

I/R: ischaemia-reperfusion; LAD: left anterior descending coronary artery; rGLP-1: recombinant GLP-1; IV: intravenous route; SC: subcutaneous route; VP: valine pyrrolide; VF: ventricular fibrillation; DPP-4: dipeptidyl peptidase-4.

Several mechanisms underlying the infarct limiting effect of GLP-1 have been proposed to be independent of weight loss.³⁶ First, GLP-1 has been shown to activate the cAMP-PKA pathway,^26,32,36 the pro-survival kinase associated with reperfusion injury signalling kinase (RISK) pathway,³⁷ including the following: PI3K, Akt, MAPK, PPARβ/δ, Nrf-2, HO-1 and Akt-p70s6K-BAD pathways.^{18,26,27,33,36,38} Second, GLP-1 has been shown to reduce oxidative stress and increase antioxidants, leading to decreased apoptosis.^26,31,33,36 Third, since proinflammatory cells such as neutrophils (PMNs) play an important role during the time of blood return to the heart,^39,40 GLP-1 has been shown to attenuate the PMN activation and accumulation in the myocardium, thus reducing injuries caused by reperfusion.⁴¹ Recent studies demonstrated that the infarct limiting effects were diminished with the administration of either GLP-1 metabolite, i.e. GLP-1 (9-36),^29,30 or when giving GLP-1 with the GLP-1R antagonist, namely GLP-1 (9-39).^26,29,30,36 Moreover, the administration of liraglutide failed to activate cardioprotective kinase in the GLP-1R depleted mice. Taken together, the effect of GLP-1 on the infarct size reduction is proposed to be a GLP-1R dependent mechanism.

Effects of GLP-1 on left ventricular function

Besides its infarct limiting effect, GLP-1 has been shown to improve left ventricular (LV) recovery from ischaemic myocardial stunning after reperfusion (Table 3). The administration of GLP-1 as a post-conditioning agent, which demonstrated a higher plasma GLP-1 level, could improve LV performance by decreasing the wall motion abnormality, and increasing the ejection fraction and LV developed pressure,^29,31 compared with giving GLP-1 as a pre-conditioning agent, which has a lower plasma GLP-1 level.³¹ Nevertheless, it is possible that the time for which GLP-1 was given as a preconditioning treatment in those studies was too short, thus allowing insufficient time for its action. This is supported by a report by Noyan-Ashraf and colleagues which demonstrated that the GLP-1 analogue required the optimal pre-treatment time and dose for the activation of the cardiac gene and protein to promote LV enhancement.³⁶ Other possible factors including routes and times of drug administration during I/R could also play an important role in this finding. Interestingly, like the infarct limiting effect, exendin-4 also improved the mechanical function in a biphasic manner.³⁰ In a clinically relevant swine model, exenatide improved regional and global systolic function.³³ In coronary artery disease patients with good LV function, a continuous infusion of rGLP-1 for 30 minutes before dobutamine stress echocardiography demonstrated an improved ejection fraction and LV regional wall function as well as mitigated post-ischaemic stunning, predominantly in the ischaemic wall segment.⁴² The beneficial effect of a 72-hour GLP-1 infusion on the post- infarction recovery, including an increased ejection fraction and improvement of both global and regional wall motion was also observed in acute myocardial infarction patients with LV ejection fraction of less than 40% after successful primary percutaneous coronary intervention.⁴³ Long-term GLP-1 infusion also improved myocardial stunning, which was characterised by enhanced LV wall motion and relaxation in I/R dogs.⁴⁴

Table 3.

Summary of the effects of GLP-1 on left ventricular function.

Animal species	Study model	Drug/dose/route	Major findings	Interpretation	References
Rabbit	I/R LCX ligation 30-min ischaemia 180-min reperfusion	GLP-1-Tf 10 mg/kg Pretreatment 12 h, SC At reperfusion, IV	1. GLP-1 level in post-ischaemic treatment significantly higher than pre-ischaemic treatment. 2. Given GLP-1-Tf at reperfusion decreased wall motion abnormality. 3. Given GLP-1-Tf at reperfusion improved ejection fraction. 4. Pretreatment with GLP-1-Tf failed to improve ejection fraction and wall motion abnormality.	GLP-1-Tf at higher concentration, post-ischaemic treatment, improved LV function by limiting myocardial stunning.	Matsubara et al.³¹
Dog	I/R Balloon LCX occlusion 10-min ischaemia 1-day reperfusion	GLP-1 1.5 pmol/kg per min, IV perfusion, during reperfusion	1. GLP-1 caused an earlier and completely recovered regional wall motion. 2. GLP-1 restored diastolic relaxation to normal. 3. GLP-1 did not improve fractional shortening. 4. GLP-1 did not improve LV contractility.	GLP-1 enhanced functional recovery from ischaemic myocardial stunning independently of changing systemic haemodynamic or global systolic function.	Nikolaidis et al.⁴⁴
Pig	I/R LCX ligation 75-min ischaemia 3-day reperfusion	Exenatide 10 µg, SC and IV, 5 min before reperfusion + 10 µg, SC, twice daily during reperfusion	1. Exenatide increased systolic wall thickening. 2. Exenatide increased fractional area shortening. 3. Exenatide increased ejection fraction. 4. Exenatide reduced myocardial stiffness.	Exenatide improved systolic function	Timmers et al.³³
Rat	I/R LAD ligation 30-min ischaemia 24-h reperfusion	Albiglutide 1, 3, 10 mg/kg per day, SC, once daily, for 3 days	1. Albiglutide increased dP/dt_max. 2. Albiglutide increased myocardial glucose uptake. 3. Albiglutide increased carbohydrate oxidation and reduced fat oxidation. 4. Albiglutide increased ejection fraction and end systolic volume.	Albiglutide increased cardiac function by improving cardiac metabolic efficiency.	Bao et al.³²
Isolated mice heart	I/R 30-min global ischaemia 40-min reperfusion	Liraglutide 0.3, 3, 30 nM, in perfusion buffer, 20 min before ischaemia 30 nM, in perfusion buffer, at reperfusion for 20 min Pretreatment with liraglutide 200 µg/kg, IP, b.i.d., 1- or 7-day	1. Acute treatment with liraglutide before or after ischaemia failed to improve LVDP. 2. Pretreatment with liraglutide for 1- or 7-day improved LVDP.	LV improvement of liraglutide required optimal dose and pretreatment time.	Noyan-Ashraf et al.³⁶
Isolated rat heart	I/R 35-min global no flow ischaemia 120-min reperfusion	VP 40 µM + GLP-1 0.3 nM, during 15 min of reperfusion	GLP-1 slightly increased LVDP, rate pressure product and maximal rate of LV systolic pressure development.	GLP- 1 + VP tended to improve LV function.	Ossum et al.²⁹
Isolated rat heart	I/R 35 min global no flow ischaemia 120-min reperfusion	VP 40 µM + GLP-1 (9-36) 0.3 nM, during 15 min of reperfusion	GLP-1 (9-36) decreased LVDP, rate pressure product and maximal rate of LV systolic pressure development.	GLP-1 metabolite acted as a strong negative inotrope in post-ischaemic hearts.	Ossum et al.²⁹
Isolated rat heart	I/R 45-min global no flow ischaemia 120-min reperfusion	Exendin-4 0.03, 0.3, 3.0 nM, for 15 min at reperfusion GLP-1 (9-36) 0.03, 0.3, 3.0 nM, for 15 min at reperfusion	1. Exendin-4 at 0.03 and 0.3 nM improved LVDP and rate pressure product during the last 60 min of reperfusion. 2. GLP-1 (9-36) at 0.03 and 0.3 nM improved LVDP and rate pressure product during the last 60 min of reperfusion. 3. GLP-1 (9-39) partly affected on beneficial effect of LV performance of exendin-4 and GLP-1 (9-36).	GLP-1 and GLP-1 (9-36) increased ventricular performance. Action of GLP-1 and GLP-1 (9-36) was mediated independently with GLP-1R.	Sonne et al.³⁰
Isolated rat heart	I/R 30-min global low flow ischaemia 30-min reperfusion	GLP-1 500 pmol/L in perfusion buffer, pretreatment 1 min before ischaemia and throughout reperfusion	1. GLP-1 enhanced LV end diastolic pressure. 2. GLP-1 increased LVDP. 3. GLP-1 increased myocardial glucose uptake. 4. GLP-1 increased GLUT-1 and GLUT-4 translocation.	GLP-1 improved post-ischaemic contractile dysfunction by enhancing myocardial glucose uptake.	Zhao et al.¹⁸
Isolated rat heart and isolated mitochondria	I/R 20-min global low flow ischaemia 30-min reperfusion	Exendin-4 1 nM/kg, SC, 6 day, once daily, after birth	Juvenile age (4–6 weeks) 1. HW, HW/BW, and HW/tibia length were similar between groups. 2. Exendin enhanced per cent recovery of LVDP. 3. Rates of state 3 and 4 respiration were comparable in control and exendin treated group. 4. Exendin did not reduce oxidative stress. 5. Exendin did not increase antioxidant, MnSOD. Adult age (9 months) 1. HW, HW/BW, and HW/tibia length were similar between groups. 2. Exendin improved recovery of LVDP. 3. Rates of state 3 respiration were lower in exendin-treated animal, while state 4 respiration was comparable. 4. Mitochondria from exendin-treated group took up less calcium.	Short course treatment with exendin-4 improved LV function in adult after I/R insult by alteration of mitochondrial phenotype which reduced rates of oxidative phosphorylation and mitochondrial calcium uptake.	Brown et al.⁴⁷
Isolated mice heart of wild type and GLP-1 R^-/-	I/R 30-min global no flow ischaemia 40-min reperfusion	GLP-1 Exendin-4 0.3, 3, 5 nM in perfusion buffer Pretreatment for 20 min before ischaemia Post-treatment for 20 min at reperfusion GLP-1 (9-36) 0.3, 3, 6 nM in perfusion buffer Pretreatment for 20 min before ischaemia Post-treatment for 20 min at reperfusion	1. Pretreatment with GLP-1 (0.3nM) and Exendin-4 (5 nM) increased LVDP in wild-type mice. 2. Pretreatment with GLP-1 (0.3 nM) increased LVDP in GLP-1R^-/- mice. 3. Pretreatment with exendin-4 failed to increase LVDP in GLP-1R^-/- mice. 4. Pretreatment with GLP-1 (9-36) worsened LV function in wild type mice. 5. Post treatment with GLP-1 (9-36) improved LVDP in both wild-type and GLP-1R^-/- mice. 6. With sitagliptin, effect of GLP-1 on LVDP was diminished in GLP-1R^-/- but improved in wild-type mice.	Effects of GLP-1 on LV performance were mediated via both GLP-1R dependent and independent pathways.	Ban et al.³⁸
Acute MI patients with EF<40%	After successful primary angioplasty	rGLP-1 1.5 pmol/kg per min 72 h after angioplasty	1. rGLP-1 improved LV ejection fraction. 2. rGLP-1 decreased global and regional wall motion score index.	Infusion of GLP-1 improved regional and global LV function in patient after successful primary angioplasty.	Nikolaidis et al.⁴³
Patients	Coronary artery disease with normal resting LV function	GLP-1 1.2 pmol/kg per min, intravenous infusion starting at 30 min before dobutamine stress echocardiography	1. GLP-1 level was increased after GLP-1 administration. 2. GLP-1 lowered plasma glucose level. 3. Insulin level was increased in GLP-1 treated group during dobutamine stress. 4. Free fatty acid level was lowered in GLP-1 treated group. 5. GLP-1 improved ejection fraction and regional wall function during peak dobutamine stress and 30 min of recovery. 6. GLP-1 had a greater beneficial effect on ischaemic than on non-ischaemic segments.	GLP-1 improved both global and regional LV performance in response to stress and also reduced post-ischaemic stunning.	Read et al.⁴²

I/R: ischaemia-reperfusion; LCX: left circumflex coronary artery; GLP-1-Tf: glucagon-like peptide-1-transferrin; SC: subcutaneous route; IV: intravenous route; LV: left ventricle; LAD: left anterior descending coronary artery; IP: intraperitoneal route; LVDP: left ventricular developed pressure; VP: valine pyrrolide; GLP-1R: GLP-1 receptor; GLUT: glucose transporter; MnSOD: manganese superoxide dismutase; HW: heart weight; BW: body weight; EF: ejection fraction; rGLP-1: recombinant GLP-1.

Surprisingly, the benefit of exenatide and GLP-1 on LV function was also observed in the presence of GLP-1R antagonist and in GLP-1R deleted mice, suggesting that the improved LV function of GLP-1 may be mediated independent of GLP-1R.^30,38 However, a recent study demonstrated that GLP-1 co-administered with sitagliptin, DPP-4 inhibitor, could not improve contractile functional recovery in GLP-1R deleted mice, whereas this treatment provided the benefit in wild-type mice.³⁸ Taken together, unlike the infarct limiting effect, the LV function amelioration of GLP-1 was mediated by both GLP-1R dependent and independent pathways. Although the administration of GLP-1 (9-36) could not reduce the infarct size,^29,30 it exerts a functional recovery benefit which might mediate through the GLP-1 (9-36)-cGMP-NO pathway, independent of GLP-1R activation.^30,38 However, the inotropic effect of GLP-1 (9-36) is still questionable.²⁹

Enhanced myocardial glucose uptake by up-regulation of glucose transporter (GLUT)-1 and GLUT-4 may be one of the underlying mechanisms to explain the beneficial effect of GLP-1 on LV functional improvement.^18,32 In a normal physiological condition, the heart mainly uses fatty acid as a fuel in maintaining its function. Reduced availability of oxygen during low-flow ischaemia reduces the heart’s ability to produce energy from fatty acid oxidation and carbohydrates. The enhancement of glycolysis through diverse mechanisms or pharmacologic interventions can delay and prevent ischaemic damage and improve the recovery of the contractile function.^45,46 GLP-1 has been shown to increase myocardial glucose uptake, which ameliorates the post-ischaemia myocardial dysfunction.^18,32 This action of GLP-1 might be used as a therapeutic target for high risk cardiovascular disease patients, especially in insulin resistant T2DM. The long-term effect of GLP-1 analogue has been demonstrated in neonatal rats receiving exenatide once daily for six days.⁴⁷ This persistent beneficial effect is mediated by an altered mitochondrial phenotype which decreased the cardiac mitochondria calcium uptake and reduced oxidative phosphorylation, resulting in improved functional recovery after ischaemia reperfusion injury. Surprisingly, the cardioprotective effect of GLP-1 and GLP-1 analogue was not associated with any improvement in haemodynamic parameters (Table 4).^{26,31–35,44,47}

Table 4.

Summary of the effects of GLP-1 on haemodynamic parameters.

Animal species	Study model	Drug/dose/route	Major findings	Interpretation	References
Rabbit	I/R LCX ligation 30-min ischaemia 180-min reperfusion	GLP-1-Tf 10 mg/kg Pretreatment 12 h, SC At reperfusion, IV	Treatment with GLP-1-Tf did not affect heart rate and mean arterial blood pressure between groups.	GLP-1-Tf did not alter haemodynamic parameters.	Matsubara et al.³¹
Pig	I/R LAD ligation 60-min ischaemia 120-min reperfusion	rGLP-1, 3 pmol/kg per min, 120 min before experiment + rGLP-1, 3 pmol/kg per min, IV perfusion during I/R rGLP-1, 3 pmol/kg per min, IV perfusion during I/R	rGLP-1 did not affect heart rate, cardiac output, mean arterial blood pressure, pulmonary artery wedge pressure and central venous pressure.	rGLP-1 did not alter haemodynamic parameters.	Kavianipour et al.³⁴
Pig	I/R Balloon LAD occlusion 40-min ischaemia 150-min reperfusion	Liraglutide Pretreatment 10 µg/kg, SC, once daily for 3 days	Liraglutide increased heart rate but had no effect on blood pressure and cardiac output.	Liraglutide slightly increased heart rate but had no effect on other haemodynamic parameters.	Kristensen et al.³⁵
Pig	I/R LCX ligation 75-min ischaemia 3-day reperfusion	Exenatide 10 µg, SC and IV 5 min before reperfusion 10 µg, SC, twice daily during reperfusion	Exenatide did not affect heart rate, mean arterial blood pressure and cardiac output.	Exenatide did not alter haemodynamic parameters.	Timmers et al.³³
Rat	I/R LAD ligation 30-min ischaemia 120-min reperfusion	Pretreated with VP 20 mg/kg, SC, 30 min before experiment + infusion with GLP-1 4.8 pmol/kg per min throughout experiment	VP + GLP-1 did not affect heart rate and mean arterial blood pressure.	GLP-1 with DPP-4 did not alter haemodynamic parameters.	Bose et al.²⁶
Dog	I/R Balloon LCX occlusion 10-min ischaemia 1-day reperfusion	GLP-1 1.5 pmol/kg per min, IV perfusion, during reperfusion	GLP-1 did not affect heart rate, coronary blood flow, mean arterial blood pressure and LV end diastolic pressure.	Long term GLP-1 infusion did not alter haemodynamic parameters.	Nikolaidis et al.⁴⁴
Isolated mice heart of wild type and GLP-1R^-/-	I/R 30-min global no flow ischaemia 40-min reperfusion	GLP-1 Exendin-4 0.3, 3, 5 nM in perfusion buffer Pretreatment for 20 min before ischaemia Post-treatment for 20 min at reperfusion GLP-1 (9-36) 0.3, 3, 6 nM in perfusion buffer Pretreatment for 20 min before ischaemia Post-treatment for 20 min at reperfusion	1. Pretreatment with GLP-1 improved pre- and post- ischaemic coronary flow. 2. Pretreatment with GLP-1 (9-36) improved pre-ischaemic coronary flow. 3. Post treatment with GLP-1 (9-36) improved post-ischaemic coronary flow. 4. GLP-1 and GLP-1 (9-36) increased cGMP level in wild-type and GLP-1R^-/- mice. 5. Exendin-4 did not produce cGMP release. 6. Functional recovery after I/R was reduced in GLP-1 treated with L-NAME, NOS inhibitor.	Vascular effects of GLP-1 were mediated via GLP-1 (9-36) and GLP-1R independent pathway, through NOS-dependent cGMP formation.	Ban et al.³⁸
Patients	Coronary artery disease with normal resting LV function	GLP-1 1.2 pmol/kg per min, IV infusion starting at 30 min before dobutamine stress echocardiography	GLP-1 did not affect heart rate, systolic and diastolic blood pressure, and rate-pressure product.	GLP-1 did not alter haemodynamic parameters.	Read et al.⁴²

I/R: ischaemia-reperfusion; LCX: left circumflex coronary artery; GLP-1-Tf: glucagon-like peptide-1-transferrin; SC: subcutaneous route; LAD: left anterior descending coronary artery; IV: intravenous route; rGLP-1: recombinant GLP-1; VP: valine pyrrolide; DPP-4: dipeptidyl peptidase-4; LV: left ventricle; GLP-1R: GLP-1 receptor; L-NAME: NG-monomethyl-L-arginine; NOS: nitric oxide synthase.

Unlike GLP-1, information regarding the effects of DPP-4 inhibitor on the I/R heart is scarce and controversial.^48–50 DPP-4 inhibitors inhibit the enzyme activity of DPP-4, resulting in decreasing degradation rate, thereby maintaining higher GLP-1 levels.^24,51,52 Although growing evidence demonstrated the infarct limiting effect of DPP-4 inhibitors (Table 5), many studies suggested that the physiological level of GLP-1 may not be sufficient to reduce the infarct size (Table 6). Besides the infarct limiting effect, the beneficial effect of DPP-4 inhibitors on LV function after I/R injury has also been documented (Table 7).

Table 5.

Summary of the beneficial effects of DPP-4 inhibitor on infarct size.

Animal species	Study model	Drug/dose/route	Major findings	Interpretation	References
Diet-induced obesity, insulin resistant rat	I/R LAD ligation 35-min ischaemia 30-min reperfusion	Vildagliptin Pretreatment 10 mg/kg per day, PO, for 4 weeks	1. Vildagliptin reduced infarct size in diet induced obesity rat by 38%. 2. Vildagliptin increased plasma GLP-1 level to normal in diet-induced obesity rat. 3. Vildagliptin increased beta cell/alpha cell ratio to normal in diet-induced obesity rat. 4. Vildagliptin increased phosphorylation of Akt and ERK at serine 42.	Vildagliptin reduced infarct size in insulin resistance rat by increased phosphorylation of Akt and ERK at serine 42.	Huisamen et al.⁵³
Rat	I/R LAD ligation 30-min ischaemia 4-hour reperfusion	Sitagliptin Pretreatment 300 mg/kg per day, PO, for 3 or 14 days	1. Pretreatment with sitagliptin for 3 and 14 days reduced infarct size by 47% and 64%, respectively. 2. Using PKA inhibitor completely abolished infarct limiting effect of sitagliptin. 3. Sitagliptin increased cAMP level.	Protective effect of sitagliptin was via cAMP-dependent PKA activation.	Ye et al.⁴⁸

I/R: ischaemia-reperfusion; LAD: left anterior descending coronary artery; PO: per oral; GLP-1: glucagon-like peptide-1; ERK: extracellular regulated kinase; PKA: protein kinase A.

Table 6.

Summary of the neutral effects of DPP-4 inhibitor on infarct size.

Animal species	Study model	Drug/dose/route	Major findings	Interpretation	References
Normoglycaemic rat	I/R LAD ligation 35-min ischaemia 30-min reperfusion	Vildagliptin Pretreatment 10 mg/kg per day, PO, for 4 weeks	Vildagliptin did not reduce infarct size in normal rat.	Vildagliptin did not reduce infarct size in normal rat.	Huisamen et al.⁵³
DPP-4^-/- mice	MI LAD ligation for 4 weeks	DPP-4^-/- mice	1. DPP-4^-/- mice had improved survival rate. 2. DPP-4^-/- mice did not have reduced infarct size. 3. pGSK3β, pANP, pAkt were increased in DPP-4^-/- mice.	DPP-4^-/- did not reduce infarct size, but improved survival rate after MI in normoglycaemia. The mechanism could be due to activation of pGSK3β, pANP and pAkt.	Sauve et al.⁴⁹
High fat diet with streptozotocin-induced diabetic mice	MI LAD ligation for 4 weeks	Sitagliptin Pretreatment 250 mg/kg per day, PO, 12 weeks	1. Sitagliptin improved survival rate. 2. Sitagliptin did not reduce infarct size. 3. Sitagliptin increased GLP-1 (7-36) amide level. 4. Sitagliptin lowered HbA1c level. 5. HO-1, ANP, pAkt increased in sitagliptin group. 6. pGSK3β tended to increase in sitagliptin-treated group.	Sitagliptin did not reduce infarct size, but improved survival rate after MI in diabetic mice. The mechanism could be due to activation of HO-1, ANP, pAkt and improved blood glucose.	Sauve et al.⁴⁹
Rat	I/R LAD ligation 30-min ischaemia 120-min reperfusion	VP 20 mg/kg, SC, 30 min before ischaemia	VP did not reduce infarct size.	Intact GLP-1 alone did not reduce infarct size.	Bose et al.²⁶
Rat	Ischaemic heart failure 12-week LAD occlusion	Vildagliptin 15 mg/kg per day, PO, 2 days prior to LAD occlusion 15 mg/kg per day, PO, beginning after LAD occlusion for 3 weeks	1. Vildagliptin increased active plasma GLP-1 level and decreased DPP-4 activity. 2. Vildagliptin did not mitigate the MI-induced decrease in capillary density. 3. Vildagliptin could not reduce cardiomyocyte size.	Early or late vildagliptin treatments had no infarct limiting effect on ischaemic cardiac remodelling.	Yin et al.⁵⁴
Isolated rat heart	I/R Left main coronary artery ligation (regional ischaemia) 35-min ischaemia 120-min reperfusion	VP Pretreatment 20 mg/L VP 20 mg/L at reperfusion	VP did not reduce infarct size whether given as preconditioning or at reperfusion.	Intact GLP-1 alone did not reduce infarct size.	Bose et al.²⁷
Isolated rat heart	I/R Left main coronary artery ligation (regional ischaemia) 35-min ischaemia 120-min reperfusion	VP 20 mg/L, in perfusion buffer, throughout experiment	VP alone did not reduce infarct size.	Intact GLP-1 alone did not reduce infarct size.	Bose et al.²⁸

I/R: ischaemia-reperfusion; LAD: left anterior descending coronary artery; PO: per oral; MI: myocardial infarction; pGSK: phosphorylated glycogen synthase kinase; pANP: phosphorylated atrial natriuretic peptide; pAkt: phosphorylated Akt; GLP-1: glucagon-like peptide-1; HbA1c: haemoglobin A1c; HO-1: heme oxygenase-1; VP: valine pyrrolide; SC: subcutaneous route; DPP-4: dipeptidyl pepetidase-4.

Table 7.

Summary of the effects of DPP-4 inhibitor on left ventricular function.

Animal species	Study model	Drug/dose/route	Major findings	Interpretation	References
Rat	Ischaemic heart failure 12-week LAD occlusion	Vildagliptin 15 mg/kg per day, PO for 2 days prior to LAD occlusion 15 mg/kg per day, PO for 3 weeks after LAD occlusion	1. Vildagliptin did not improve ejection fraction and fractional shortening. 2. Progressive LV dilatation and wall thinning after MI was attenuated in vildagliptin-treated groups. 3. Vildagliptin did not improve dP/dt_max and dP/dt_min.	Early and late treatment with vildagliptin had no beneficial effect on LV function.	Yin et al.⁵⁴
Isolated mice heart	I/R 30-min global no flow ischaemia 40-min reperfusion	Sitagliptin 20 mg/kg, IP, 12 h and 1 h prior to heart excision DPP-4^-/- mice Sitagliptin 5 µmol/L, in perfusion buffer, for 20 min before I/R insult	1. Sitagliptin improved LVDP in normoglycaemic mice. 2. LVDP was increased in DPP-4^-/- mice compared with DPP-4^+/+ mice. 3. Administration of sitagliptin immediately before I/R injury failed to improve LVDP in normoglycaemic mice.	Genetic deletion and pharmacological inhibition of DPP-4 activity improved LV function. Acute reduction of cardiac DPP-4 activity was not sufficient to improve LV function.	Sauve et al.⁴⁹
Patients	Coronary artery disease and preserved LV function	Sitagliptin 100 mg, single PO	1. Sitagliptin increased plasma GLP-1 level. 2. Sitagliptin lowered plasma glucose level. 3. Insulin level was comparable between groups. 4. Free fatty acid level was comparable between groups. 5. Sitagliptin improved ejection fraction and regional wall function during peak dobutamine stress and 30 min of recovery. 6. Sitagliptin had a greater beneficial effect on ischaemic than on non-ischaemic segments.	Sitagliptin improved both global and regional LV performance in response to stress and also reduced post-ischaemic stunning.	Read et al.⁵⁰

LAD: left anterior descending coronary artery; PO: per oral; LV: left ventricle; MI: myocardial infarction; I/R: ischaemia-reperfusion; IP: intraperitoneal route; LVDP: left ventricle developed pressure; DPP-4: dipeptidyl pepetidase-4; GLP-1: glucagon-like peptide-1.

Effects of DPP-4 inhibitor on the infarct size

As DM increases cardiovascular risk including myocardial infarction, pretreatment with vildagliptin, DPP-4 inhibitor, has been shown to attenuate the infarct size in insulin resistant rats.⁵³ This cardioprotective effect was also observed in normoglycaemic rats with pretreatment of sitagliptin.⁴⁸ A longer period of pre-treatment with sitagliptin resulted in smaller infarct size, suggesting that the plasma drug level might influence its cardioprotective effect. The infarct limiting mechanism of DPP-4 inhibitor in these studies was proposed to be due to the activation of Akt and cAMP-PKA pro-survival kinase in RISK pathway as observed in GLP-1 administration.^48,53 However, some studies demonstrated that prolonged availability of intact GLP-1 caused by a DPP-4 inhibitor failed to demonstrate the infarct limiting effect.^26–28,54 Moreover, inhibition or reduction of DPP-4 activity using DPP-4 deleted mice or pretreatment with sitagliptin before ischaemia in high fat diet-induced diabetic mice could not reduce the infarct size, but improved the survival rate by activation of cardioprotection kinase such as GSK3β, ANP and Akt.⁴⁹ These discrepant results suggest that the different animal models, the duration of ischaemia in the heart models and the minimal dose for a specific time may play a pivotal role in the reduction of the infarct size. Tables 5 and 6 summarise significant effects of DPP-4 inhibitors on the infarct size.

Effects of DPP-4 inhibitor on left ventricular function

DPP-4 inhibitors also exert a cardioprotective effect by the improvement of post-ischaemia myocardial stunning. Table 7 summarises the effects of DPP-4 inhibitors on LV function. In DPP-4 deleted mice and mice pretreated with sitagliptin for 12 hours prior to aortic occlusion, improved LV developed pressure after I/R injury was observed.⁴⁹ However, acute treatment with sitagliptin for 20 minutes prior to I/R insult failed to improve ventricular performance.⁴⁹ The discrepancy in these findings could be due to the differences in the time of drug administration as well as study models (in vivo versus ex vivo), and might suggest that the benefit of DPP-4 inhibitor required an optimal time and an intact cardiovascular system process. However, a recent report in rats with ischaemic heart failure demonstrated that early or late treatment with vildagliptin had no beneficial effect on ventricular performance.⁵⁴ In a clinical study, single dose treatment with sitagliptin improved regional and global wall function, which improved post-ischaemic stunning in patients with coronary artery disease awaiting revascularisation.⁵⁰ These improvements are independent of insulin⁵⁰ or haemodynamic parameter alterations.^49,50,53 Table 8 summarises the effect of DPP-4 inhibitors on haemodynamic parameters.

Table 8.

Summary of the effects of DPP-4 inhibitor on haemodynamic parameters.

Animal species	Study model	Drug/dose/route	Major findings	Interpretation	References
Mice	MI LAD ligation for 4 weeks	DPP-4^-/- mice	Aortic flow and mitral flow were comparable between DPP-4^-/- mice and DPP-4^+/+ mice.	Genetic inhibition of DPP-4 activity did not alter haemodynamic parameters.	Sauve et al.⁴⁹
Mice	MI LAD ligation for 4 days	Sitagliptin 250 mg/kg per day, PO, for 11 days	Aortic flow and mitral flow were comparable between sitagliptin and control group.	Pharmacological inhibition of DPP-4 activity did not alter haemodynamic parameters.	Sauve et al.⁴⁹
Rat	Ischaemic heart failure 12-week LAD occlusion	Vildagliptin 15 mg/kg per day, PO for 2 days prior to LAD occlusion 15 mg/kg per day, PO for 3 weeks after LAD occlusion	Vildagliptin did not alter heart rate, systolic and diastolic blood pressure, LV systolic and end diastolic pressure.	Vildagliptin had no beneficial effect on haemodynamic parameters.	Yin et al.⁵⁴
Isolated rat heart	I/R 45-min global low flow ischaemia 30-min reperfusion	Vildagliptin Pretreatment 10 mg/kg per day, PO, for 4 weeks	Vildagliptin did not improve basal aortic output and basal coronary flow in both normal and insulin resistant rat.	Vildagliptin did not alter haemodynamic parameters.	Huisamen et al.⁵³
Patients	Coronary artery disease and preserved LV function	Sitagliptin 100 mg, single oral dose	Sitagliptin did not affect heart rate, systolic and diastolic blood pressure, and rate-pressure product.	Sitagliptin did not alter haemodynamic parameters.	Read et al.⁵⁰

MI: myocardial infarction; LAD: left anterior descending coronary artery; DPP-4: dipeptidyl pepetidase-4; PO: per oral; LV: left ventricle; I/R: ischaemia-reperfusion.

Conclusion

Growing evidence suggests that incretin exerts a cardioprotective effect during I/R injury. The infarct limiting effect is mediated through GLP-1R, while LV function improvement is mediated through both GLP-1R dependent and independent (via GLP-1 (9-39)) pathways. The underlying mechanisms were due to the activation of prosurvival kinase, increased antioxidant and myocardium glucose utilisation, reduction of oxidative stress and pro-apoptotic kinase, and attenuation proinflammatory cell activation and accumulation in the myocardium. Although many mechanisms have been proposed, the exact mechanisms have never been fully elucidated. Therefore, further investigations are required to determine the cardioprotective mechanisms of incretin. Ultimately, large clinical trials are the essential step to validate those effects reported in animal studies and to warrant their clinical use in the I/R condition.

Footnotes

Funding

This work was supported by the Thailand Research Fund Royal Golden Jubilee PhD Project (KC and NC) and the Thailand Research Fund (grants nos RTA5280007 (NC) and BRG5480003 (SC)).

Conflicts of interest

No conflicts of interest have been declared.

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Cardioprotective effects of incretin during ischaemia-reperfusion

Abstract

Keywords

Introduction

Effects of GLP-1 on the infarct size

Effects of GLP-1 on left ventricular function

Effects of DPP-4 inhibitor on the infarct size

Effects of DPP-4 inhibitor on left ventricular function

Conclusion

Footnotes

Funding

Conflicts of interest

References