The potential effects of anti-diabetic medications on myocardial ischemia–reperfusion injury

Abstract

Heart disease and stroke account for 65% of the deaths in people with diabetes mellitus (DM). DM and hyperglycemia cause systemic inflammation, endothelial dysfunction, a hypercoagulable state with impaired fibrinolysis and increased platelet degranulation, and reduced coronary collateral blood flow. DM also interferes with myocardial protection afforded by preconditioning and postconditioning. Newer anti-diabetic agents should not only reduce serum glucose and HbA1c levels, but also improve cardiovascular outcomes. The older sulfonylurea agent, glyburide, abolishes the benefits of ischemic and pharmacologic preconditioning, but newer sulfonylurea agents, such as glimepiride, may not interfere with preconditioning. GLP-1 analogs and sitagliptin, an oral dipeptidyl peptidase IV inhibitor, limit myocardial infarct size in animal models by increasing intracellular cAMP levels and activating protein kinase A, whereas metformin protects the heart by activating AMP-activated protein kinase. Both thiazolidinediones (rosiglitazone and pioglitazone) limit infarct size in animal models. The protective effect of pioglitazone is dependent on downstream activation of cytosolic phospholipase A(2) and cyclooxygenase-2 with subsequent increased production of 15-epi-lipoxin A(4), prostacyclin and 15-d-PGJ(2). We conclude that agents used to treat DM have additional actions that have been shown to affect the ability of the heart to protect itself against ischemia-reperfusion injury in preclinical models. However, the effects of these agents in doses used in the clinical setting to minimize ischemia-reperfusion injury and to affect clinical outcomes in patients with DM have yet to be shown. The clinical implications as well as the mechanisms of protection should be further studied.

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

“…The antidiabetic therapy may either interfere with the cardioprotective signaling pathway, thereby blocking the "conditioning" strategy, or it may mimic the "conditioning" strategy, thereby inducing cardioprotection (reviewed in Ferdinandy et al, 2007;Ye et al, 2011). Through these effects, there is the potential for antidiabetic therapies to impact on long-term cardiac outcomes in diabetic patients.…”

“…The activation of either the sarcolemmal or mitochondrial K ATP channel within the cardiomyocyte is a critical step in the signaling pathway underlying both preconditioning and postconditioning . It is well established in the preclinical literature that some long-acting antidiabetic sulfonylureas (such as tolbutamide and glibenclamide), which act by blocking K ATP channel activity in the pancreas to promote insulin release, also interfere with the signaling pathway underlying preconditioning and postconditioning by antagonizing K ATP channel activity within the cardiomyocyte (reviewed in Ye et al, 2011). However, some of the newer shorter-acting antidiabetic sulfonylureas, such as gliclazide and glimepiride, do not appear to interfere with cardioprotection (Wu et al, 2007).…”

Time to Give Up on Cardioprotection?

“…180 However, patients with coronary artery disease have also been exposed to risk factors and comorbidities that increase the sensitivity to myocardial ischemia/ reperfusion injury and attenuate cardioprotective signaling, such as hypertension, 181,182 hypercholesterolemia, 183,184 and diabetes mellitus. [185][186][187][188][189] Patients with coronary artery disease have endothelial dysfunction. The endothelium, however, is important in mediating the cardioprotective effect of remote ischemic conditioning.…”

“…[202][203][204] Calcium antagonist pretreatment is associated with cardioprotection, 205 but calcium antagonists seem not to interfere with conditioning. 206 In antidiabetic treatment, there are the sulfonylureas that interfere with cardioprotective signaling because they inhibit ATP-dependent potassium channel activation, 187,207 whereas some glitazones, 208,209 the glucagonlike peptide 1 analog exenatide, [210][211][212] and some dipeptidyl peptidase 4 inhibitors 213,214 protect per se. Only high-dose aspirin that blocks both cyclo-oxygenase 1 and 2 seems to interfere with cardioprotection.…”

Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: Rationale for the active-comparator CAROLINA trial

“…However, the results of some studies have led to uncertainty about their durability and long-term CV safety, which may potentially be related to the fact that SUs not only bind to the SU receptor (SUR) subunit (subtype SUR1) of the potassium ATP (K ATP ) channel in the beta-cell membrane, but may also bind to the SUR receptor (subtype SUR2) on cardiac myocytes and on endothelial cells, and thus have direct effects on CV function. 29 The controversy regarding the CV safety profile of SUs started with the highly criticized University Group Diabetes Program (UGDP), conducted in the 1960s that first gave rise to concerns about the safety of the firstgeneration SU, tolbutamide. In this study, a significantly increased risk of all-cause and CV mortality was observed among participants receiving this SU versus placebo.…”