Review Article
Endocrinol Metab 2016;31:239-244 http://dx.doi.org/10.3803/EnM.2016.31.2.239 pISSN 2093-596X · eISSN 2093-5978
Diabetes Drugs and Cardiovascular Safety Ji Cheol Bae Division of Endocrinology and Metabolism, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea Diabetes is a well-known risk factor of cardiovascular morbidity and mortality, and the beneficial effect of improved glycemic control on cardiovascular complications has been well established. However, the rosiglitazone experience aroused awareness of potential cardiovascular risk associated with diabetes drugs and prompted the U.S. Food and Drug Administration to issue new guidelines about cardiovascular risk. Through postmarketing cardiovascular safety trials, some drugs demonstrated cardiovascular benefits, while some antidiabetic drugs raised concern about a possible increased cardiovascular risk associated with drug use. With the development of new classes of drugs, treatment options became wider and the complexity of glycemic management in type 2 diabetes has increased. When choosing the appropriate treatment strategy for patients with type 2 diabetes at high cardiovascular risk, not only the glucose-lowering effects, but also overall benefits and risks for cardiovascular disease should be taken into consideration. Keywords: Diabetes mellitus; Cardiovascular diseases; Heart failure; Hypoglycemic agents
INTRODUCTION Cardiovascular (CV) disease is a highly prevalent complication and the major cause of premature death in patients with type 2 diabetes [1]. The effect of improved glycemic control on CV complication has been well established through clinical trials and meta-analyses [2-5]. However, several studies have suggested that some antidiabetic drugs increase CV risk, despite being effective at lowering blood glucose in type 2 diabetes [69]. For this reason, new diabetes agents are required to demonstrate CV safety, showing robust CV outcome data from randomized, controlled trials in order to grant approvals. On the other hand, these regulatory requirements might also provide the opportunity for some of drugs in CV outcome trials to be tested for CV benefits [1]. Received: 3 May 2016, Revised: 19 May 2016, Accepted: 24 May 2016 Corresponding author: Ji Cheol Bae Division of Endocrinology and Metabolism, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, 158 Paryong-ro, Masanhoewon-gu, Changwon 51353, Korea Tel: +82-55-290-1540, Fax: +82-55-290-1014, E-mail:
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We will discuss the evidence of the CV risk associated with thiazolidinedione (TZD) use, which aroused awareness of potential CV risk associated with diabetes agents and prompted the U.S. Food and Drug Administration (FDA) to issue new guidelines about CV risk [10]. This study will also review the published or currently ongoing CV safety trial of the dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP1) receptor agonist, and sodium glucose cotransporter 2 (SGLT2) inhibitor.
THIAZOLIDINEDIONES Rosiglitazone Adverse data from a meta-analysis published in New England Journal of Medicine in 2007 evoked concern about a possible Copyright © 2016 Korean Endocrine Society This is an Open Access article distributed under the terms of the Creative Com mons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribu tion, and reproduction in any medium, provided the original work is properly cited.
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increased CV risk associated with rosiglitazone use [7,10]. Using a fixed-effects analytic model with data from 42 randomized clinical trials, this analysis concluded that rosiglitazone was associated with an approximately 43% increased risk of myocardial infarction (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.03 to 1.98) and an approximately 64% increased risk of CV death (OR, 1.64; 95% CI, 0.98 to 2.74) [7]. The interpretation of these study results have been debated extensively [11,12]. These meta-analyses consisted of predominantly small, short-term, nonadjudicated treatment trials in lower-risk populations [7,13]. Nissen’s analysis used the number of events rather than time to event without consideration of follow-up, and some trials with no events were excluded. None of the trial included in the reports focused primarily on CV safety in patients treated with rosiglitazone [11-13]. Furthermore, studies were combined on the basis of a lack of statistical heterogeneity, despite substantial variability in control groups, inclusion criteria, follow-up, and outcome assessment. Indeed, other researchers have analyzed the same group of studies using different statistical methods and found no link between heart attack and rosiglitazone [11]. Nevertheless, additional meta-analyses suggested an increased risk of adverse CV events among patients with type 2 diabetes treated with rosiglitazone [6,14,15]. Due to this possible association with myocardial infarction, rosiglitazone was withdrawn from the European market by the European Medicines Agency in 2010 [16]. At the same time, the FDA imposed restrictions on the prescription and use of the diabetes drug rosiglitazone [17]; the drug has also been removed from the Korean market. In 2013, the FDA lifted restrictions on the prescription and use of rosiglitazone after re-evaluation of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial, which showed no increase in the risk of CV morbidity or mortality attributable to rosiglitazone [18,19]. The RECORD trial is the only completed prospective trial to evaluate CV safety in patients treated with rosiglitazone [13]. The rosiglitazone experience aroused awareness of potential CV risk associated with diabetes agents and prompted the FDA to issue new guidelines about CV risk. The approval process for new agents must include a demonstration of no unacceptable increase in CV risk [10]. This requires a meta-analysis of important CV events in phase 2/3 to achieve an upper 95% CI 1.8, additional phase 3 safety studies are required before resubmission for marketing authorization. If the overall risk-benefit balance supports drug approval but the upper CI lies between 1.3 and 1.8, then a postmarketing CV trial usually required to demonstrate an upper 95% CI
