Exenatide Reduces Infarct Size and Improves Cardiac Function in a Porcine Model of Ischemia and Reperfusion Injury

Timmers, Leo; Henriques, José P.S.; Kleijn, Dominique P.V. de; DeVries, J. Hans; Kemperman, Hans; Steendijk, Paul; Verlaan, Cees W.J.; Kerver, Marjolein; Piek, Jan J.; Doevendans, Pieter A.; Pasterkamp, Gérard; Hoefer, Imo E.

doi:10.1016/j.jacc.2008.10.033

Cited by 421 publications

(361 citation statements)

References 33 publications

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“…A functional GLP‐1 receptor (GLP‐1R) is highly expressed in the heart. GLP‐1R agonists and DPP‐4 inhibitors have beneficial effects on the cardiovascular system (Ban et al., 2008; Noyan‐Ashraf et al., 2009; Timmers et al., 2009). Previous studies have shown that GLP‐1 and its analogs protected the heart against ischemia‐reperfusion injury and diabetes mellitus (Tate, Robinson, Green, McDermott & Grieve, 2016; Wang et al., 2013).…”

Section: Introductionmentioning

confidence: 99%

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

Wang

et al. 2018

Aging Cell

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SummaryLipotoxicity cardiomyopathy is the result of excessive accumulation and oxidation of toxic lipids in the heart. It is a major threat to patients with diabetes. Glucagon‐like peptide‐1 (GLP‐1) has aroused considerable interest as a novel therapeutic target for diabetes mellitus because it stimulates insulin secretion. Here, we investigated the effects and mechanisms of the GLP‐1 analog exendin‐4 and the dipeptidyl peptidase‐4 inhibitor saxagliptin on cardiac lipid metabolism in diabetic mice (DM). The increased myocardial lipid accumulation, oxidative stress, apoptosis, and cardiac remodeling and dysfunction induced in DM by low streptozotocin doses and high‐fat diets were significantly reversed by exendin‐4 and saxagliptin treatments for 8 weeks. We found that exendin‐4 inhibited abnormal activation of the (PPARα)‐CD36 pathway by stimulating protein kinase A (PKA) but suppressing the Rho‐associated protein kinase (ROCK) pathway in DM hearts, palmitic acid (PA)‐treated rat h9c2 cardiomyocytes (CMs), and isolated adult mouse CMs. Cardioprotection in DM mediated by exendin‐4 was abolished by combination therapy with the PPARα agonist wy‐14643 but mimicked by PPARα gene deficiency. Therefore, the PPARα pathway accounted for the effects of exendin‐4. This conclusion was confirmed in cardiac‐restricted overexpression of PPARα mediated by adeno‐associated virus serotype‐9 containing a cardiac troponin T promoter. Our results provide the first direct evidence that GLP‐1 protects cardiac function by inhibiting the ROCK/PPARα pathway, thereby ameliorating lipotoxicity in diabetic cardiomyopathy.

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Section: Introductionmentioning

confidence: 99%

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

Wang

et al. 2018

Aging Cell

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“…These drugs lower glucose levels by inhibiting the secretion of glucagon, promoting the release of insulin in response to hyperglycemia, slowing gastric emptying, and augmenting satiety. 14 On the basis of some evidence of cardioprotection in preliminary studies in animal models 15,16 and in pilot studies of myocardial ischemia 17,18 and heart failure in humans, 19 it was postulated 20,21 that in addition to improving glycemic control and promoting weight loss, GLP-1-receptor agonists may improve cardiovascular outcomes.…”

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confidence: 99%

Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome

et al. 2015

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BACKGROUND: Cardiovascular morbidity and mortality are higher among patients with type 2 diabetes, particularly those with concomitant cardiovascular diseases, than in most other populations. We assessed the effects of lixisenatide, a glucagon-like peptide 1-receptor agonist, on cardiovascular outcomes in patients with type 2 diabetes who had had a recent acute coronary event. METHODS: We randomly assigned patients with type 2 diabetes who had had a myocardial infarction or who had been hospitalized for unstable angina within the previous 180 days to receive lixisenatide or placebo in addition to locally determined standards of care. The trial was designed with adequate statistical power to assess whether lixisenatide was noninferior as well as superior to placebo, as defined by an upper boundary of the 95% confidence interval for the hazard ratio of less than 1.3 and 1.0, respectively, for the primary composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina. RESULTS: The 6068 patients who underwent randomization were followed for a median of 25 months. A primary end-point event occurred in 406 patients (13.4%) in the lixisenatide group and in 399 (13.2%) in the placebo group (hazard ratio, 1.02; 95% confidence interval [CI], 0.89 to 1.17), which showed the noninferiority of lixisenatide to placebo (P<0.001) but did not show superiority (P=0.81). There were no significant between-group differences in the rate of hospitalization for heart failure (hazard ratio in the lixisenatide group, 0.96; 95% CI, 0.75 to 1.23) or the rate of death (hazard ratio, 0.94; 95% CI, 0.78 to 1.13). Lixisenatide was not associated with a higher rate of serious adverse events or severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions than was placebo. CONCLUSIONS: In patients with type 2 diabetes and a recent acute coronary syndrome, the addition of lixisenatide to usual care did not significantly alter the rate of major cardiovascular events or other serious adverse events. (Funded by Sanofi; ELIXA ClinicalTrials.gov number, NCT01147250.). Jean-Claude (2015). Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.

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“…Paradoxically, following meta-analytic data suggesting an increased cardiovascular risk with rosiglitazone [6], this class of agents has now undergone more rigorous long-term cardiovascular study, and the overall conclusion is that the long-term risk-benefit profile of these drugs is uncertain. The problem for newer agents such as incretin-based treatments, which have shown very promising effects in animal studies [7,8] and surrogate effects in clinical trials [9], is that solid evidence from long-term clinical trials will not be available for several years, as is the case with any newer agent that appears on the horizon.…”

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confidence: 99%

Consensus guidelines, algorithms and care of the individual patient with type 2 diabetes

Nolan

2010

Diabetologia

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Despite advances in understanding of the pathophysiology of type 2 diabetes and the abundance of expert reviews on its treatment, a large gap remains between what is generally believed and what is actually known about treatments for diabetes and their long-term effects. Over a relatively short recent interval the ADA and the EASD have jointly published successive consensus algorithms for the management of hyperglycaemia in patients with type 2 diabetes [1,2]. The authors of both the 2006 and 2009 consensus algorithms acknowledged in their introductions that while numerous reviews on the treatment of type 2 diabetes have been published in recent years, 'practitioners are often left without a clear pathway of therapy to follow' [1,2]. The most recent algorithm, with its two-tiered approach to metabolic management, has clearly not solved this problem and has itself provoked further debate and commentary [3,4], including most recently the critique by Schernthaner and colleagues [5] published in the current issue of Diabetologia.The most recent contributors, rather than proposing a further, newer algorithm for diabetes treatment (perhaps we should be grateful that further guidelines have not been proposed), take issue with the 'expert opinion' approach adopted by the ADA/EASD authors and argue instead for an evidence-based strategy, taking into account the impact of various treatments on clinically important endpoints (such as macrovascular events). They put forward the case for individual optimisation of care of the patient with the goals of sustained blood glucose control and the reduction of complications and cardiovascular risk. Clearly no sensible clinician would dispute this case, and this includes those who have generated the previous guidelines and algorithms. Following the ancient principle of 'first, do no harm', the overall goal for a good doctor must be the improved care and quality of life of the individual patient. However, equally clearly there is a problem with treatment algorithms for type 2 diabetes based on 'expert opinion'. The article by Schernthaner and colleagues [5] raises some important limitations inherent in this approach and, in the process, points to some of the broader challenges in modern diabetes care. Their conclusion is that the 2009 treatment algorithm is not in fact based on evidence. This debate is useful for those who care for patients with diabetes, in that it emphasises the importance of evidence, while drawing our attention to the wide areas where the answers are not yet known, and where the evidence does not yet exist and may not exist for some time. The prevalence of diabetes continues to increase and actual treatment decisions and choices face individual patients and their doctors on a daily basis. How these decisions are best made in the real world may ultimately be through a pragmatic individual patient plan, taking account of the best available evidence, the stage in life of the patient, the biological stage of progression of their diabetes and the relative priorities of...

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Exenatide Reduces Infarct Size and Improves Cardiac Function in a Porcine Model of Ischemia and Reperfusion Injury

Abstract: These data identify exenatide as a potentially effective compound to reduce infarct size in adjunction to reperfusion therapy in patients with acute MI.

Cited by 421 publications

References 33 publications

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome

Consensus guidelines, algorithms and care of the individual patient with type 2 diabetes

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