Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA^®)

Abstract

CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (NCT01243424) is an ongoing, randomized trial in subjects with early type 2 diabetes and increased cardiovascular risk or established complications that will determine the long-term cardiovascular impact of linagliptin versus the sulphonylurea glimepiride. Eligible patients were sulphonylurea-naïve with HbA1c 6.5%–8.5% or previously exposed to sulphonylurea (in monotherapy or in a combination regimen <5 years) with HbA1c 6.5%–7.5%. Primary outcome is time to first occurrence of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina. A total of 631 patients with primary outcome events will be required to provide 91% power to demonstrate non-inferiority in cardiovascular safety by comparing the upper limit of the two-sided 95% confidence interval as being below 1.3 for a given hazard ratio. Hierarchical testing for superiority will follow, and the trial has 80% power to demonstrate a 20% relative cardiovascular risk reduction. A total of 6041 patients were treated with median type 2 diabetes duration 6.2 years, 40.0% female, mean HbA1c 7.2%, 66% on 1 and 24% on 2 glucose-lowering agents and 34.5% had previous cardiovascular complications. The results of CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes may influence the decision-making process for selecting a second glucose-lowering agent after metformin in type 2 diabetes.

Is It Time to Change the Type 2 Diabetes Treatment Paradigm? No! Metformin Should Remain the Foundation Therapy for Type 2 Diabetes

“…They therefore will not provide relevant information as to the preferred monotherapy for type 2 diabetes. One exception is a trial comparing the DPP-4 inhibitor linagliptin to the sulfonylurea glimepiride, but also upon background glucose-lowering therapy that will likely commonly involve metformin (35). The National Institutes of Health's Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) trial is testing mainly the durability of several options added to metformin (glimepiride, sitagliptin, liraglutide, and insulin glargine) (36).…”

Efficacy and Safety of Linagliptin in Subjects With Long-standing Type 2 Diabetes Mellitus (>10 Years): Evidence From Pooled Data of Randomized, Double-blind, Placebo-controlled, Phase III Trials

“…In addition, the CAROLINA ® (Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes; NCT01243424) study has enrolled 6103 patients with T2DM at high cardiovascular risk or with cardiovascular complications. 41 Baseline results indicate that overall, 59% of patients have a reported T2DM duration of 45 years. CAROLINA is the only longterm cardiovascular outcomes trial of a DPP-4 inhibitor to include an active sulfonylurea comparator, and it will also include a long-term β-cell function substudy.…”

Interpretation of cardiovascular outcome trials in type 2 diabetes needs a multiaxial approach

“…Over the next years, with several CV outcome trials due to report (Figure 1) [22][23][24][25][26][27][28][29] , an opportunity for great learnings is at our doorsteps. Since some trials might even contribute to paradigm shifts in our approach to T2D management, it is important to contextualize the results to the study populations in scope taking into account T2D disease duration, degree of vasculopathy, duration of the intervention, and the mode of action of the intervention (Figure 2).…”