Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: Rationale for the active-comparator CAROLINA trial

Abstract

Sulphonylureas (SUs) are widely used glucose-lowering agents in type 2 diabetes mellitus (T2DM) with apparent declining efficacy over time. Concerns have been raised from observational retrospective studies on the cardiovascular (CV) safety of SUs but there are few long-term data on CV outcomes from randomized controlled trials (RCTs) involving the use of this class of agents. Most of the observational studies and registry data are conflicting and vary with study population and methodology used for analyses. To address the SU controversy, we reviewed the recently published literature (until end of the year 2011) to evaluate the impact of SUs on CV outcomes in modern, longer-term (≥72 weeks) RCTs where they were compared in a head-to-head fashion versus an active comparator or were used as part of a treatment strategy. We identified 15 trials and found no report of an increase in the incidence of CV events with the use of SUs. However, the available data are limited, and, most importantly, there was no adequately powered formal head-to-head CV outcome trial designed to address CV safety. Since SUs are still being advocated as second-line therapy added-on to metformin, as one of several classes, and in certain circumstances first-line therapy in T2DM management, definitive data from a dedicated RCT addressing the CV safety question with SUs would be informative. Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA) is such a trial, ongoing since November 2010, and is currently the largest head-to-head CV outcome trial that involves a comparison of a SU (glimepiride) with a dipeptidyl peptidase-4 (DPP-4) inhibitor (linagliptin) and will provide a unique perspective with respect to CV outcomes with these two commonly used agents.

Incidence of Pancreatitis and Pancreatic Cancer in a Randomized Controlled Multicenter Trial (SAVOR-TIMI 53) of the Dipeptidyl Peptidase-4 Inhibitor Saxagliptin

“…The possible risk should be properly judged in the context of the favorable outcome of these cases and the overall proven safety record of this group of drugs. This question will be further determined by the results of other ongoing DPP-4 inhibitors prospective outcome trials (34,35).…”

Once daily versus twice daily Linagliptin effect on glycemic levels in type 2 diabetes mellitus- an observational study

“…6,7 A clear answer on the safety profile of CV in relation to linagliptin will be provided by the cardiovascular outcome study of linagliptin versus glimepiride in patients with type 2 diabetes (CAROLINA), the results are expected to report between 2017 and 2018. 8 Linagliptin can be used without dose adjustment in patients with reduced renal function. Among Asian populations, metformin is used under dosage due to risk of gastrointestinal issues.…”

Diabetes-Old Therapies Revisited

“…Two studies that are taking place, the TOSCA.IT [53] and [54], Carolina may clarify by comparing the sulfonylureas with pioglitazone and linagliptin, respectively. Other studies will be needed to evaluate the differences between the various types of SU´s.…”