Julio Rosenstock, MD

First results from the Cardiovascular Safety of Linagliptin (CAROLINA) outcomes trial comparing linagliptin and glimepiride will be presented at 4:30 p.m. Monday in W-3001 (West, Level 3). ADAMeetingNews.org asked CAROLINA principal investigator Julio Rosenstock, MD, to discuss the background, objective, and significance of the outcomes trial. Dr. Rosenstock is Director of the Dallas Diabetes Research Center at Medical City Dallas and Clinical Professor of Medicine at the University of Texas Southwestern Medical Center.

Study Background

Dr. Rosenstock: Since 2008, cardiovascular (CV) safety outcomes trials have been required by the U.S. Food and Drug Administration for all new glucose-lowering agents prior to approval. However, all of these trials were and are being conducted in a placebo-controlled setting design with no active comparators. CAROLINA is the longest cardiovascular safety outcomes trial to date, and it’s the only one with a head-to-head active comparator design.

Objective/Methods

Dr. Rosenstock: CAROLINA is a randomized, double-blind, active-controlled, multicenter clinical trial designed to test the cardiovascular safety of a DDP-4 inhibitor (linagliptin) versus a sulfonylurea (glimepiride). The trial involved 6,033 adults with type 2 diabetes observed for a median duration of more than six years. The trial included adults with early type 2 diabetes: Adults with a median disease duration of 6.2 years who either received no treatment or received one or two glucose-lowering agents, e.g., metformin. The primary outcome of the study is the time to first occurrence of CV death, non-fatal myocardial infarction (MI), excluding silent MI, or non-fatal stroke.

Significance

Dr. Rosenstock: The results of CAROLINA have the potential to provide meaningful evidence to help the decision-making process for clinicians and their patients when selecting a second- or third-line therapy to metformin. The CAROLINA trial may also provide crucial new evidence regarding the cardiovascular safety of sulfonylureas, an issue that has been long-debated and highly controversial for more than 50 years.

I think people are looking forward to these results because head-to-head active control studies are important to establish efficacy, safety, and effectiveness, and we also have an opportunity to learn about the long-term durability of the effects of linagliptin and sulfonylureas, specifically glimepiride, which is widely used.