CAROLINA: Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes

Summary

The aim of the study is to investigate the longterm impact on cardiovascular morbidity and mortality, relevant efficacy parameters (e.g., glycaemic parameters) and safety (e.g., weight and hypoglycaemia) of treatment with linagliptin in patients with type 2 diabetes at elevated cardiovascular risk receiving usual care, and compare outcome against glimepiride.

Timeline

Start

2010-11-11

Primary completion

2018-08-21

Completion

2018-08-21

Outcome

Met primary endpoint

registry analysis (non-inferiority test); Linagliptin vs Glimepiride; p <0.0001; Hazard Ratio (HR) 0.98 (95.47% CI 0.84 to 1.14) reads as unknown NCT01243424 ↗

paper P < .001 for noninferiority), meeting the noninferiority criterion but not superiority reads as unknown PMID 31536101 ↗

release “announced CAROLINA® (CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 diabetes) met its primary endpoint” reads as met primary endpoint lilly.com ↗

Publications

• Marx N, Kolkailah AA, Rosenstock J, Johansen OE, Cooper ME, Alexander JH, Toto RD, Wanner C, Espeland MA, Mattheus M, Schnaidt S, Perkovic V, Gollop ND, McGuire DK. Hypoglycemia and Cardiovascular Outcomes in the CARMELINA and CAROLINA Trials of Linagliptin: A Secondary Analysis of Randomized Clinical Trials. JAMA Cardiol. 2024 Feb 1;9(2):134-143. doi: 10.1001/jamacardio.2023.4602.
• Balasubramanian P, Kernan WN, Sheth KN, Ofstad AP, Rosenstock J, Wanner C, Zinman B, Mattheus M, Marx N, Inzucchi SE. Baseline Cardiovascular Risk Factor Control in Patients With Type 2 Diabetes and Coronary Disease Versus Stroke: Secondary Analysis of Cardiovascular Outcome Trials. Stroke. 2023 Aug;54(8):2013-2021. doi: 10.1161/STROKEAHA.122.042053. Epub 2023 Jul 14.
• Dar MS, Wanner C, Marx N, Ofstad AP, Mattheus M, Kaspers S, Beg SA. Cardiovascular outcomes trial data from EMPA-REG OUTCOME, CAROLINA and CARMELINA: Assessment of a novel staging system for type 2 diabetes. Diabetes Obes Metab. 2023 May;25(5):1372-1384. doi: 10.1111/dom.14989. Epub 2023 Mar 6.
• Verhagen C, Janssen J, Minderhoud CA, van den Berg E, Wanner C, Passera A, Johansen OE, Biessels GJ. Chronic kidney disease and cognitive decline in patients with type 2 diabetes at elevated cardiovascular risk. J Diabetes Complications. 2022 Oct;36(10):108303. doi: 10.1016/j.jdiacomp.2022.108303. Epub 2022 Aug 31.
• Verhagen C, Janssen J, Biessels GJ, Johansen OE, Exalto LG. Females with type 2 diabetes are at higher risk for accelerated cognitive decline than males: CAROLINA-COGNITION study. Nutr Metab Cardiovasc Dis. 2022 Feb;32(2):355-364. doi: 10.1016/j.numecd.2021.10.013. Epub 2021 Oct 27.
• Biessels GJ, Verhagen C, Janssen J, van den Berg E, Wallenstein G, Zinman B, Espeland MA, Johansen OE. Effects of linagliptin vs glimepiride on cognitive performance in type 2 diabetes: results of the randomised double-blind, active-controlled CAROLINA-COGNITION study. Diabetologia. 2021 Jun;64(6):1235-1245. doi: 10.1007/s00125-021-05393-8. Epub 2021 Feb 9.
• Rosenstock J, Kahn SE, Johansen OE, Zinman B, Espeland MA, Woerle HJ, Pfarr E, Keller A, Mattheus M, Baanstra D, Meinicke T, George JT, von Eynatten M, McGuire DK, Marx N; CAROLINA Investigators. Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial. JAMA. 2019 Sep 24;322(12):1155-1166. doi: 10.1001/jama.2019.13772.
• Janssen J, van den Berg E, Zinman B, Espeland MA, Geijselaers SLC, Mattheus M, Johansen OE, Biessels GJ. HbA1c, Insulin Resistance, and beta-Cell Function in Relation to Cognitive Function in Type 2 Diabetes: The CAROLINA Cognition Substudy. Diabetes Care. 2019 Jan;42(1):e1-e3. doi: 10.2337/DC18-0914. No abstract available.
• Chilton R. Linagliptin versus glimepiride add-on for the long-term treatment of Type 2 diabetes mellitus. Expert Rev Endocrinol Metab. 2013 Jul;8(4):345-349. doi: 10.1586/17446651.2013.811849.
• Biessels GJ, Janssen J, van den Berg E, Zinman B, Espeland MA, Mattheus M, Johansen OE; CAROLINA(R) investigators. Rationale and design of the CAROLINA(R) - cognition substudy: a randomised controlled trial on cognitive outcomes of linagliptin versus glimepiride in patients with type 2 diabetes mellitus. BMC Neurol. 2018 Jan 15;18(1):7. doi: 10.1186/s12883-018-1014-7.
• Marx N, Rosenstock J, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, Espeland MA, Bluhmki E, Mattheus M, Ryckaert B, Patel S, Johansen OE, Woerle HJ. Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA(R)). Diab Vasc Dis Res. 2015 May;12(3):164-74. doi: 10.1177/1479164115570301. Epub 2015 Mar 15.

Drugs

Evaluation	Drug	Modality	Dose	Route
Subject	Glimepiride	Small molecule	1 mg	Oral
Subject	Glimepiride	Small molecule	4 mg	Oral
Subject	Linagliptin	Unknown	5 mg	Oral

Indications