Effects of Metformin Therapy on Coronary Endothelial Dysfunction in Patients With Prediabetes With Stable Angina and Nonobstructive Coronary Artery Stenosis: The CODYCE Multicenter Prospective Study

1946 Diabetes Care Volume 42, October 2019 Effects of Metformin Therapy on Coronary Endothelial Dysfunction in Patients With Prediabetes With Stable Angina and Nonobstructive Coronary Artery Stenosis: The CODYCE Multicenter Prospective Study Celestino Sardu,1 Pasquale Paolisso,1 Cosimo Sacra,2 Ciro Mauro,3 Fabio Minicucci,3 Michele Portoghese,4 Maria Rosaria Rizzo,1 Michelangela Barbieri,1 Ferdinando Carlo Sasso,1 Nunzia D’Onofrio,5 Maria Luisa Balestrieri,5 Paolo Calabrò,6 Giuseppe Paolisso,1 and Raffaele Marfella1 Diabetes Care 2019;42:1946–1955 | https://doi.org/10.2337/dc18-2356 OBJECTIVE To evaluate the effect of metformin therapy on coronary endothelial function and major adverse cardiac events (MACE) in patients with prediabetes with stable angina and nonobstructive coronary stenosis (NOCS). 1 CARDIOVASCULAR AND METABOLIC RISK RESEARCH DESIGN AND METHODS Metformin therapy may be needed to reduce coronary heart disease risk in patients with prediabetes. A total of 258 propensity score–matched (PSM) patients with stable angina undergoing coronary angiography were enrolled in the study. Data from 86 PSM subjects with normoglycemia (NG), 86 PSM subjects with prediabetes (pre-DM), and 86 PSM subjects with prediabetes treated with metformin (pre-DM metformin) were analyzed. During coronary angiography, NOCS was categorized by luminal stenosis <40% and fractional flow reserve >0.80. In addition, we assessed the endothelial function, measuring coronary artery diameter of left anterior descending coronary (LAD) at baseline and after the infusion of acetylcholine, by means of an intracoronary Doppler guide wire. MACE, as cardiac death, myocardial infarction, and heart failure, was evaluated at 24 months of follow-up. RESULTS At baseline, NG patients had a lower percentage of LAD endothelial dysfunction compared with pre-DM patients (P < 0.05). The pre-DM patients had a higher percentage of endothelial LAD dysfunction as compared with the pre-DM metformin patients (P < 0.05). At the 24th month of follow-up, MACE was higher in pre-DM versus NG (P < 0.05). In pre-DM metformin patients, MACE was lower compared with pre-DM patients (P < 0.05). CONCLUSIONS Metformin therapy may reduce the high risk of cardiovascular events in pre-DM patients by reducing coronary endothelial dysfunction. Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania “Luigi Vanvitelli,” Naples, Italy 2 Department of Cardiovascular Diseases, John Paul II Research and Care Foundation, Campobasso, Italy 3 Department of Cardiovascular Diseases, Antonio Cardarelli Hospital, Naples, Italy 4 UOC Division of Cardiovascular Surgery, Sassari Hospital, Sassari, Italy 5 Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” Naples, Italy 6 Division of Clinical Cardiology, AORN Sant’Anna e San Sebastiano, Caserta, Italy Corresponding author: Celestino Sardu, drsarducele@ gmail.com Received 13 November 2018 and accepted 22 January 2019 Clinical trial reg. no. NCT03553030, clinicaltrials .gov This article is featured in a podcast available at http://www.diabetesjournals.org/content/diabetescore-update-podcasts. © 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license. care.diabetesjournals.org Prediabetes is an intermediate metabolic state between normoglycemia and diabetes (1). Prediabetes includes patients with impaired glucose tolerance and impaired fasting glucose and hemoglobin A1c (HbA1c) values between 5.7% and 6.4% (39–46 mmol/mol) (1). Worldwide, more than 400 million people have prediabetes, and projections indicate that by 2030 more than 470 million people will have prediabetes (2). Moreover, in a recent survey based on HbA1c results, 33.6% of outpatients (out of 1.16 million outpatient visits analyzed) had prediabetes (2). Intriguingly, ,1% of those patients whose HbA1c tests showed prediabetes were recognized and diagnosed as such by clinicians (1,2). To date, with a growing trend, prediabetes affects .38% of people in the adult population, and it is associated with an increased risk of developing diabetes (3). Although some prospective studies have shown that prediabetes is associated with an increased risk of cardiovascular disease (4,5), other studies have not found a similar association (6–8). However, several previous metaanalyses have led to conflicting conclusions (3,9,10), due to differences in end point assessments and study inclusion criteria. In this context, a very recent study showed that prediabetes was not associated with an increased risk of subclinical coronary atherosclerosis (stenosis severity $50%) evaluated transversally by coronary computed tomographic angiography (11). Moreover, Liu et al. (12) showed that among patients with stable, new-onset coronary heart disease (stenosis severity $50%), the increased cardiovascular risk in prediabetes is largely affected by the coexistence of hypertension rather than prediabetes per se. Therefore, these studies did not provide any evidence about the role of prediabetes on cardiovascular outcomes in the early coronary atherosclerotic disease progression, such as those found in nonobstructive coronary stenosis (NOCS) (stenosis severity ,50%), or assess the specific mechanisms transducing prediabetes environmental stimuli in coronary atherosclerotic disease progression. In this context, the common link between prediabetes and coronary heart disease may be represented by hyperglycemia and insulin resistance, both leading to the early insurgence of coronary artery Sardu and Associates dysfunction (13,14). Therefore, these pathological mechanisms may cause coronary artery dysfunction also in the absence of obstructive coronary stenosis. Recently, Sara et al. (15) showed that patients with stable angina, stable coronary artery disease (CAD), and NOCS have endothelial dysfunction, which is consequently linked to an increased rate of worse prognosis and cardiac mortality. However, a great disagreement exists in literature about the correlation between prediabetes, endothelial dysfunction, and clinical outcomes in stable CAD-NOCS. Thus, this study was designed to identify differences in endothelial coronary function, as well as major adverse cardiac events (MACE) at 24 months of follow-up, between patients with prediabetes and normoglycemic (NG) patients with stable angina and NOCS. In addition, American Diabetes Association (ADA) guidelines suggest that prediabetes be treated with hypoglycemic drugs such as metformin to control glucose homeostasis and to reduce the risk of diabetes development and the linked worse prognosis (16). Intriguingly, less is known about the effect of metformin to reduce the coronary endothelial dysfunction and the consequent improved clinica (...truncated)