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Cited by 212Diabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and LipoproteinsDiabetes Management and Research

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

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Marx, Nikolaus, Rosenstock, Julio, Kahn, Steven E, Zinman, Bernard, Kastelein, John J, Lachin, John M, Espeland, Mark A, Bluhmki, Erich +5 more·2015·Diabetes and Vascular Disease Research
DOI 10.1177/1479164115570301PMC PMC4390606
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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 HbA 1c 6.5%–8.5% or previously exposed to sulphonylurea (in monotherapy or in a combination regimen <5 years) with HbA 1c 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.

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  • The CAROLINA study demonstrated noninferiority between a DPP-4 inhibitor, linagliptin, and a sulfonylurea, glimepiride, on cardiovascular outcomes despite lower rates of hypoglycemia in the linagliptin treatment group.

    “In addition, the CAROLINA (Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Type 2 Diabetes) study demonstrated noninferiority between a DPP-4 inhibitor, linagliptin, and a sulfonylurea, glimepiride, on cardiovascular outcomes despite lower rates of hypoglycemia in the linagliptin treatment group (254).”

    From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [254]

    The Discussion describes CAROLINA as an ongoing trial designed to test cardiovascular noninferiority, not one that had demonstrated it. It attributes the lower hypoglycemia incidence to a former study, not to results from CAROLINA. (LLM, conf=0.91)

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  • The CAROLINA study demonstrated noninferiority between linagliptin and glimepiride on cardiovascular outcomes despite lower rates of hypoglycemia in the linagliptin treatment group.

    “The CAROLINA (Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Type 2 Diabetes) study demonstrated noninferiority between a DPP-4 inhibitor, linagliptin, and a sulfonylurea, glimepiride, on cardiovascular outcomes despite lower rates of hypoglycemia in the linagliptin treatment group (267).”

    From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [267]

    The Discussion describes CAROLINA as an ongoing trial designed to test cardiovascular noninferiority, not a trial that had demonstrated it. It attributes the lower incidence of hypoglycaemia with linagliptin to a former study, not to CAROLINA results. (LLM, conf=0.91)

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Research works printed but not linked: 21

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Authors
Marx, N., Rosenstock, J., Kahn, S. E., Zinman, B., Kastelein, J. J., Lachin, J. M., Espeland, M. A., Bluhmki, E., Mattheus, M., Ryckaert, B., Patel, S., Johansen, O. E., & Woerle, H.-J.
Affiliations
  • Universitätsklinikum Aachen (DE)
  • The University of Texas Southwestern Medical Center (US)
  • University of Washington (US)
  • Mount Sinai Hospital (CA)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • George Washington University (US)
  • Atrium Health Wake Forest Baptist (US)
  • Boehringer Ingelheim (Germany) (DE)
  • Boehringer Ingelheim (Belgium) (BE)
  • Boehringer Ingelheim (United Kingdom) (GB)
  • Boehringer Ingelheim (Norway) (NO)
Corresponding author
Marx, Nikolaus
ORCID
Venue
Diabetes and Vascular Disease Research
Publisher
SAGE Publications
Published
2015-03-15
Volume
12
Issue
3
Pages
164-174
ISSN
  • 1479-1641 (ISSN-L)
  • 1752-8984
DOI
10.1177/1479164115570301
PMC
PMC4390606
OpenAlex
W2133980496
Cited by
212
References
2
Citations by year
2025: 6 · 2024: 3 · 2023: 5 · 2022: 7 · 2021: 12 · 2020: 19 · 2019: 45 · 2018: 42 · 2017: 30 · 2016: 24 · 2015: 18 · 2014: 1
FWCI
33.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes and Vascular Disease Research (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (acceptedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • RWTH Publications (RWTH Aachen) (submittedVersion)
Funders
  • Eli Lilly and Company
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK017047)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords
linagliptin, glimepiride, type 2 diabetes, cardiovascular outcomes, DPP-4 inhibitors, sulfonylureas, cardiovascular safety, non-inferiority, myocardial infarction, stroke, cardiovascular mortality, metformin
MeSH terms
Linagliptin, Adult, Aged, Aged, 80 and over, Blood Glucose, Cardiovascular Diseases, Clinical Protocols, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Glycated Hemoglobin, Humans, Male, Middle Aged, Research Design, Risk Factors, Sulfonylurea Compounds, Biomarkers, Treatment Outcome, Sample Size, Patient Selection, Dipeptidyl Peptidase 4, Incretins, Dipeptidyl-Peptidase IV Inhibitors

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