Metformin in non-diabetic patients presenting with ST elevation myocardial infarction: rationale and design of the glycometabolic intervention as adjunct to primary percutaneous intervention in ST elevation myocardial infarction (GIPS)-III trial

Abstract

Background: Left ventricular dysfunction and the development of heart failure is a frequent and serious complication of myocardial infarction. Recent animal experimental studies suggested that metformin treatment reduces myocardial injury and preserves cardiac function in non-diabetic rats after experimental myocardial infarction. We will study the efficacy of metformin with the aim to preserve left ventricular ejection fraction in non-diabetic patients presenting with ST elevation myocardial infarction (STEMI).

Methods: The Glycometabolic Intervention as adjunct to Primary percutaneous intervention in ST elevation myocardial infarction (GIPS)-III trial is a prospective, single center, double blind, randomized, placebo-controlled trial. Three-hundred-and-fifty patients, without diabetes, requiring primary percutaneous coronary intervention (PCI) for STEMI will be randomized to metformin 500 mg twice daily or placebo treatment and will undergo magnetic resonance imaging (MRI) after 4 months. Major exclusion criteria were prior myocardial infarction and severe renal dysfunction. The primary efficacy parameter is left ventricular ejection fraction 4 months after randomization. Secondary and tertiary efficacy parameters include major adverse cardiac events, new onset diabetes and glycometabolic parameters, and echocardiographic diastolic function. Safety parameters include renal function deterioration and lactic acidosis.

Conclusions: The GIPS-III trial will evaluate the efficacy of metformin treatment to preserve left ventricular ejection fraction in STEMI patients without diabetes.

Trial registration: ClinicalTrials.gov NCT01217307.

Fig. 1

metformin resulted in a relative improvement in left ventricular ejection fraction of 52 % compared to placebo. MI: myocardial infarction; *P < 0.05 vs. sham group; # P < 0.05 vs. placebo group. Adapted with permission from: Fig. 2 from Meimei Yin, Iwan CC van der Horst, Joost P van Melle, Cheng Qian, Wiek H van Gilst, Herman HW Silljé, and Rudolf A de Boer. Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure. Am J Physiol Heart Circ Physiol August 2011 301:(2) H459–H468

Fig. 2

visualization of the proposed cardioprotective mechanism of action of metformin in the human heart after myocardial infarction, resulting in improved systolic and diastolic function. In experimental models metformin has been consistently associated with enhanced phosphorylation of AMP activated protein kinase (AMPK) [–24]. In the myocardium, characterized by high energy demands and low energy reserves, AMPK plays a pivotal role in maintaining metabolic homeostasis [–21]. Metformin-induced AMPK phosphorylation may be mediated by inhibition of complex 1 of the respiratory chain, by upstream activation of the tumor suppressor gene liver kinase B1 (LKB1), or by decreased AMP–deaminase activity [–24]. AMPK phosphorylation leads to activation of the Reperfusion Injury Salvage Kinase (RISK) pathway including phospatidylinositol-3-kinase (PI3K) and Akt pathways [17, 26], upregulation of the tumor suppressor gene p53 [27], inhibition of mammalian target of rapamycin (mTOR) [19], and upregulation of endothelial nitric oxide synthase (eNOS) [1, 13]. Activation of the RISK pathway and eNOS improves mitochondrial function and inhibits opening of the mitochondrial permeability transition pore (mPTP) [26]. The mPTP is a major mediator of myocardial reperfusion injury. Opening of the mPTP results in ATP depletion and cell death [25, 26]. Further, prevention of mPTP opening stimulates mitochondrial respiration, improving ATP availability and cellular function [25]. Upregulated p53 and inhibited mTOR, partly RISK pathway mediated, are associated with decreased cellular vulnerability by preventing post-mitotic cell death and improved resilience to ischemia related injury [19, 27]. Metformin mediated eNOS production, next to increasing nitric oxide production, enhances sodium pump activity causing decreased intracellular calcium levels [1]. In infarcted tissue, this may attenuate microvascular obstruction and thereby prevent mPTP mediated cell death [28]. In functional myocardium, optimized calcium handling results in improved contractility and relaxation [1]. Further, independent of AMPK, metformin inhibits transforming growth factor (TGF)-β1 myocardial expression, decreasing collagen synthesis and preventing fibrosis [29]. Metformin may also attenuate cardiac fibrosis by directly inhibiting advanced glycation endproduct (AGE) formation [30]. Also, metformin is associated with a decrease in dipeptidyl peptidase-4 activity and an increase in circulating levels of glucagon-like peptide 1 [31]. In a porcine model of ischemia and reperfusion injury, stimulation with a analogue (exenatide) resulted in a reduction of infarct size [32]. Another target of metformin may be the increase of glucose utilisation of the heart. The adult heart mainly relies on fatty acids utilisation, and switches back to glucose when damaged. However, metabolic flexibility of the failing heart is limited, and facilitation of glucose utilisation by metformin via increase of glucose transporters (GLUT-1 and GLUT-4) may explain its salutary effects on the cardiac function [12, 33]

Fig. 3

Flow chart of the GIPS-III trial. STEMI, ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; LVEF, left ventricular ejection fraction; MRI magnetic resonance imaging; OGTT oral glucose tolerance testing