Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2015 May;12(3):164-74.
doi: 10.1177/1479164115570301. Epub 2015 Mar 15.

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

Nikolaus Marx  1 , Julio Rosenstock  2 , Steven E Kahn  3 , Bernard Zinman  4 , John J Kastelein  5 , John M Lachin  6 , Mark A Espeland  7 , Erich Bluhmki  8 , Michaela Mattheus  9 , Bart Ryckaert  10 , Sanjay Patel  11 , Odd Erik Johansen  12 , Hans-Juergen Woerle  9
Affiliations
Randomized Controlled Trial

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

Nikolaus Marx et al. Diab Vasc Dis Res. 2015 May.

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.

Keywords: Type 2 diabetes; cardiovascular complications; dipeptidyl-peptidase-4 inhibitor; macrovascular; sulphonylurea.

PubMed Disclaimer

Conflict of interest statement

Declaration of conflicting interests: N.M. has served as a consultant to AstraZeneca, Amgen, BMS, Boehringer Ingelheim, Merck, Novo Nordisk, Roche and Sanofi-Aventis. He has received grant support from Merck and Boehringer Ingelheim. In addition, he has served as a speaker for AstraZeneca, Amgen, Bayer, BMS, Boehringer Ingelheim, Lilly, Merck, Mitsubishi Tanabe Pharma Corporation, Novartis, Novo Nordisk, Pfizer, Roche and Sanofi-Aventis. J.R. has served on scientific advisory boards and received honorarium or consulting fees from Sanofi, Novo Nordisk, Eli Lilly, GlaxoSmithKline, Takeda, Merck, Daiichi Sankyo, Janssen, Novartis, Boehringer Ingelheim, MannKind, Intarcia and Lexicon. In addition, he has received grants or research support from Merck, Pfizer, Sanofi, Novo Nordisk, Roche, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Amylin, Janssen, Daiichi Sankyo, MannKind, Boehringer Ingelheim, Intarcia and Lexicon. S.E.K. has served as a consultant for Boehringer Ingelheim, Elcelyx, Eli Lilly, GlaxoSmithKline, Intarcia, Janssen, Merck, Novo Nordisk, Receptos and Takeda. B.Z. has served as a consultant for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Takeda and Sanofi. He has received grant support from Merck, Novo Nordisk and Boehringer Ingelheim. J.J.K. has acted as a consultant and received honouraria from the following companies: Aegerion, Amgen, AstraZeneca, Atheronova, Boehringer Ingelheim, Catabasis, Cerenis, CSL Behring, Dezima Pharmaceuticals, Eli Lilly, Esperion, Genzyme, Isis, Merck, Novartis, Omthera, Pronova, Regeneron, Sanofi, The Medicines Company, UniQure and Vascular Biogenics. J.M.L. has during the past year consulted with Boehringer Ingelheim, Gilead, Janssen, Lilly, Merck and Novartis. M.A.E. has been a consultant for Boehringer Ingelheim, Takeda Pharmaceuticals, Terumo Medical Corporation and Amgen. E.B., M.M., B.R., S.P., O.E.J. and H.-J.W. are employees of BI, the developer of linagliptin. All authors contributed to the development of the manuscript and read and approved the final manuscript.

Figures

Figure 1.
Figure 1.
CAROLINA study design.
See this image and copyright information in PMC

References

    1. Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med 2011; 154: 602–613. - PMC - PubMed
    1. Food and Drug Administration (Center for Drug Evaluation and Research). Guidance for industry: diabetes mellitus – evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformati... (2008, accessed 18 October 2014).
    1. Meinert CL, Knatterud GL, Prout TE, et al. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes 1970; 19(Suppl.): 789–830. - PubMed
    1. Ye Y, Perez-Polo JR, Aguilar D, et al. The potential effects of anti-diabetic medications on myocardial ischemia-reperfusion injury. Basic Res Cardiol 2011; 106: 925–952. - PubMed
    1. Rosenstock J, Marx N, Kahn SE, et al. Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the active-comparator CAROLINA® trial. Diabetes Vasc Dis Re 2013; 10: 289–301. - PubMed

Publication types

MeSH terms

Associated data