DIABETESRESEARCHANDCLINICALPRACTICE 86S (2009) S53 – S56 How to interpret results of the HEART2D trial? Ivan Tkᡠc a , Zvonko Mili´ cevi´ c b, *, György Jermendy c a Department of Medicine 4, L. Pasteur Teaching Hospital, Šafárik University in Košice, Faculty of Medicine, Košice, Slovakia b Eli Lilly Regional GMBH, Vienna, Austria c Medical Department, Bajcsy-Zsilinszky Teaching Hospital, Budapest, Hungary ARTICLE INFO ABSTRACT Keywords: Type 2 diabetes mellitus Cardiovascular disease HEART2D study Glucose lowering treatment HEART2D was a multinational, randomized, controlled trial designed to compare the ef- fects of prandial insulin versus basal insulin on risk for subsequent cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) after acute myocardial infarction (MI). Trial design was based on the hypothesis that 2.5 mmol/L postprandial blood glucose (BG) dif- ference between groups would result in risk reduction of 19 to 23% over the planned follow up period (18–36 mo) in the group with lower postprandial BG. One thousand one hundred and fifteen (1115) patients were randomized [prandial strategy (N = 557), basal strategy (N = 558)]. HEART2D was stopped after futility rule implementation at the fourth interim analy- sis. The risk of a first combined adjudicated CV events in the prandial group (N = 174, 31.2%) and basal (N = 181, 32.4%) groups was similar (HR = 0.98; 95% CI [0.8, 1.21]). The results of HEART2D left the question of the role of postprandial hyperglycemia in diabetic CV disease unanswered. Here, we discuss possible reasons for this outcome, in- cluding characteristics of daily BG profiles in the two treatment groups, event rate, risk factors other than standard CV risk factors and glycemic variables. The main reasons for this outcome of HEART2D study could be smaller than expected on-study differences be- tween the study groups in postprandial hyperglycemia, and low event rate. Further trials with larger patient populations and improved designs, focusing also on diabetic patients with lower cardiovascular risk and lower baseline HbA 1c levels are needed in order to shed more light on this important clinical problem. © 2009 Elsevier Ireland Ltd. All rights reserved. 1. Objectives of HEART2D and trial design The Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes In Patients With Type 2 Diabetes Mellitus (HEART2D) Trial was designed to assess the effect of two different insulin regimens on CV outcomes in a group of patients with T2D who survived acute myocardial infarction (MI) within approximately 18 days before randomization [1]. Patients were randomized to two different insulin strategies: (a) postprandial group received short-acting insulin analog * Address for correspondence: Dr. Zvonko Mili´ cevi ´ c, Eli Lilly Re- gional, Kölblgasse 8-10, 1030 Vienna, Austria. Tel.: +43 1-711-78- 236, fax +43 1-711-78-259. E-mail address: milicevic_zvonko@lilly.com (Z. Mili´ cevi ´ c). 0168-8227/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. lispro before each main meal, targeting postprandial blood glucose (BG) of <7.5 mmol/L; (b) basal group received basal insulin (NPH or glargine) once daily in the evening, targeting fasting/premeal BG of <6,7 mmol/L [2]. Both groups aimed at hemoglobin A 1c (HbA 1c ) <7%. Oral antihyperglycemia agents were not allowed any time during the trial. Primary efficacy measure was a combined outcome of CV death, nonfatal MI, nonfatal stroke, hospitalization for acute coronary syndrome (HACS) and coronary revascularization. Hazards in the two groups were analyzed and compared using the time-to-event approach. The rationale for the trial design was based upon the epidemiological evidence of a significant association be- tween post-challenge hyperglycemia and the risk of death and/or MI in individuals with early glucose abnormalities in