Assessment of associations between hypoglycemia and cardiovascular outcomes in the randomized CARMELINA and CAROLINA trials of the antihyperglycemic medication linagliptin

Kolkailah, Ahmed A., Marx, Nikolaus, Rosenstock, Julio, Johansen, Odd Erik, Cooper, Mark E., Alexander, John H., Toto, Robert, Wanner, Christoph, Espeland, Mark A., Mattheus, Michaela, Schnaidt, Sven, Perkovic, Vlado, Gollop, Nicholas D. and McGuire, Darren K. (2022) Assessment of associations between hypoglycemia and cardiovascular outcomes in the randomized CARMELINA and CAROLINA trials of the antihyperglycemic medication linagliptin. Circulation, 146. ISSN 0009-7322

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Abstract

Introduction: Bidirectional associations between hypoglycemia and cardiovascular (CV) outcomes were evaluated in 2 CV outcome trials of the DPP-4 inhibitor, linagliptin. Methods: CARMELINA and CAROLINA trials evaluated CV outcomes with linagliptin vs placebo or glimepiride, respectively, in adults with type 2 DM at high CV ± kidney risk; of the 2, CARMELINA was longer duration/higher risk cohort. The primary outcome for both trials was CV death, myocardial infarction (MI), or stroke (3P-MACE), with heart failure (HHF) added to the primary outcome for the present analyses. Hypoglycemia was defined as plasma glucose <54 mg/dL; severe hypoglycemia defined as needing external help. Associations between the first hypoglycemic episode and subsequent CV events, and conversely, between non-fatal CV events (MI, stroke, HHF) and subsequent hypoglycemic episodes, were assessed using multivariable Cox proportional hazards models. Sensitivity analyses explored the risk of CV events within 60 days after each hypoglycemic episode. Results: In CARMELINA, there was an association between hypoglycemia and subsequent 3P-MACE + HHF (adjusted HR: 1.23; 95% CI 1.04-1.46), and between non-fatal CV events and subsequent hypoglycemia (adjusted HR: 1.39; 95% CI 1.06-1.83). In CAROLINA, there was no significant association between hypoglycemia and subsequent 3P-MACE + HHF (adjusted HR: 1.00; 95% CI 0.76-1.32), nor between non-fatal CV events and subsequent hypoglycemia (adjusted HR: 1.44; 95% CI 0.96-2.16) (Fig). In analyses of CV events occurring within 60 days after hypoglycemia, in both trials, there was either no association observed or too few events to analyze. Conclusion: The observed bidirectional associations between hypoglycemia and CV outcomes in CARMELINA and no significant associations in CAROLINA challenge the notion that hypoglycemia causes adverse CV events, but rather suggest that both hypoglycemia and CV events identify vulnerable patients at risk for both.

Item Type:	Article
Faculty \ School:	Faculty of Science > School of Mathematics Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	LivePure Connector
Date Deposited:	09 Jan 2023 12:32
Last Modified:	09 Jan 2023 12:32
URI:	https://ueaeprints.uea.ac.uk/id/eprint/90471
DOI:

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