Transitioning to active-controlled trials to evaluate cardiovascular safety and efficacy of medications for type 2 diabetes

(2022) 21:163 McGuire et al. Cardiovascular Diabetology https://doi.org/10.1186/s12933-022-01601-w Cardiovascular Diabetology Open Access METHODOLOGY Transitioning to active‑controlled trials to evaluate cardiovascular safety and efficacy of medications for type 2 diabetes Darren K. McGuire1*, David D’Alessio2, Stephen J. Nicholls3, Steven E. Nissen4, Jeffrey S. Riesmeyer5, Imre Pavo6, Shanthi Sethuraman5, Cory R. Heilmann5, John J. Kaiser5 and Govinda J. Weerakkody5 Abstract Cardiovascular (CV) outcome trials (CVOTs) of type 2 diabetes mellitus (T2DM) therapies have mostly used randomized comparison with placebo to demonstrate non-inferiority to establish that the investigational drug does not increase CV risk. Recently, several glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter 2 inhibitors (SGLT-2i) demonstrated reduced CV risk. Consequently, future T2DM therapy trials could face new ethical and clinical challenges if CVOTs continue with the traditional, placebo-controlled design. To address this challenge, here we review the methodologic considerations in transitioning to active-controlled CVOTs and describe the statistical design of a CVOT to assess non-inferiority versus an active comparator and if non-inferiority is proven, using novel methods to assess for superiority versus an imputed placebo. Specifically, as an example of such methodology, we introduce the statistical considerations used for the design of the “Effect of Tirzepatide versus Dulaglutide on Major Adverse Cardiovascular Events (MACE) in Patients with Type 2 Diabetes” trial (SURPASS CVOT). It is the first activecontrolled CVOT assessing antihyperglycemic therapy in patients with T2DM designed to demonstrate CV efficacy of the investigational drug, tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 RA, by establishing non-inferiority to an active comparator with proven CV efficacy, dulaglutide. To determine the efficacy margin for the hazard ratio, tirzepatide versus dulaglutide, for the composite CV outcome of death, myocardial infarction, or stroke (MACE-3), which is required to claim superiority versus an imputed placebo, the lower bound of efficacy of dulaglutide compared with placebo was estimated using a hierarchical Bayesian meta-analysis of placebo-controlled CVOTs of GLP-1 RAs. SURPASS CVOT was designed so that when the observed upper bound of the 95% confidence interval of the hazard ratio is less than the lower bound of efficacy of dulaglutide, it demonstrates non-inferiority to dulaglutide by preserving at least 50% of the CV benefit of dulaglutide as well as statistical superiority of tirzepatide to a theoretical placebo (imputed placebo analysis). The presented methods adding imputed placebo comparison for efficacy assessment may serve as a model for the statistical design of future active-controlled CVOTs. Keywords: Type 2 diabetes mellitus, Antihyperglycemic, Cardiovascular, Non-inferiority trial, Imputed placebo *Correspondence: 1 Division of Cardiology, University of Texas Southwestern Medical Center and Parkland Health and Hospital System, 5323 Harry Hines Blvd, Dallas, TX 75235‑8830, USA Full list of author information is available at the end of the article Introduction In 2008, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) issued guidance for the evaluation of cardiovascular (CV) safety of new antihyperglycemic therapies for type 2 diabetes mellitus (T2DM) [1, 2]. Based on this guidance, new investigational drugs for the treatment of T2DM were required © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. McGuire et al. Cardiovascular Diabetology (2022) 21:163 to demonstrate no increased risk of major adverse CV events (MACE) compared with placebo. The standard for CV safety was statistically defined by achieving a relative risk compared with placebo, with an upper bound of 95% confidence interval (CI) of less than 1.8 for initial application and 1.3 for final approval. Over the past decade, results from CV outcome trials (CVOTs) evaluating several new medication classes for T2DM such as dipeptidyl peptidase-4 inhibitors (DPP4i), basal insulins, alpha-glucosidase inhibitors, glucagonlike peptide-1 receptor agonists (GLP-1 RA), and sodium glucose cotransporter-2 inhibitors (SGLT-2i) have been reported [3–9]. Only two of these trials [8, 9] compared the investigational medications with antihyperglycemic medications as active comparators, which were added to standard clinical care of patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) or multiple CV risk factors. In addition, a pragmatic openlabel randomized active comparator TOSCA.IT trial evaluated CV outcomes of pioglitazone compared with sulfonylureas (glibenclamide, glimepiride or gliclazide) in patients with T2DM [10]. None of these active comparators (glimepiride, glibenclamide, gliclazide nor insulin glargine) had proven cardiovascular efficacy before their use in these CVOTs. However, numerous trials of SGLT-2i and GLP-1 RA medications have demonstrated reduction in MACE and/or fewer hospitalizations due to heart failure and/or reduction in risk for kidney disease progression [3–7, 11–14]. These results satisfied the regulatory requirements for evidence of CV safety and furthermore, their superior CV and kidney efficacy provided the basis for indications to use these agents to reduce CV and/or kidney disease risk. The demonstration of beneficial effects of antihyperglycemic medications on CV risk in patients with T2DM has been widely recognized as a major advance, changing the clinical practice guidelines and consensus, recommendations of professional societies to emphasize prioritized use of SGLT-2i and GLP-1 RA in patients with or at high risk of CV disease [15–19]. This favorable new therapeutic landscape, on the other hand, presents significant challenges for the desig (...truncated)