Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk.

dc.contributor.author

Rosenstock, Julio

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Perkovic, Vlado

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Alexander, John H

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Cooper, Mark E

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Marx, Nikolaus

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Pencina, Michael J

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Toto, Robert D

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Wanner, Christoph

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Zinman, Bernard

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Baanstra, David

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Pfarr, Egon

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Mattheus, Michaela

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Broedl, Uli C

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Woerle, Hans-Juergen

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George, Jyothis T

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von Eynatten, Maximilian

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McGuire, Darren K

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CARMELINA® investigators

dc.date.accessioned

2021-05-10T18:08:39Z

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2021-05-10T18:08:39Z

dc.date.issued

2018-03-14

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2021-05-10T18:08:38Z

dc.description.abstract

BACKGROUND:Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA® trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk. METHODS:CARMELINA® is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5-10.0% (48-86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, ≥ 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA® was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided α-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure. RESULTS:Between July 2013 and August 2016, 6980 patients were randomized and took ≥ 1 dose of study drug (40.6, 33.1, 16.9, and 9.4% from Europe, South America, North America, and Asia, respectively). At baseline, mean ± SD age was 65.8 ± 9.1 years, HbA1c 7.9 ± 1.0%, BMI 31.3 ± 5.3 kg/m2, and eGFR 55 ± 25 mL/min/1.73 m2. A total of 5148 patients (73.8%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 m2 or macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common. CONCLUSIONS:CARMELINA® will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk. Trial registration ClinicalTrials.gov identifier-NCT01897532; registered July 9, 2013.

dc.identifier

10.1186/s12933-018-0682-3

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1475-2840

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1475-2840

dc.identifier.uri

https://hdl.handle.net/10161/22865

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eng

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Springer Science and Business Media LLC

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Cardiovascular diabetology

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10.1186/s12933-018-0682-3

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CARMELINA® investigators

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Kidney

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Humans

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Diabetic Nephropathies

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Kidney Failure, Chronic

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Cardiovascular Diseases

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Diabetes Mellitus, Type 2

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Disease Progression

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Blood Glucose

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Glomerular Filtration Rate

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Treatment Outcome

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Cause of Death

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Risk Factors

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Double-Blind Method

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Research Design

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Time Factors

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Aged

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Middle Aged

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Female

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Male

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Renal Insufficiency, Chronic

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Dipeptidyl-Peptidase IV Inhibitors

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Biomarkers

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Linagliptin

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Glycated Hemoglobin A

dc.title

Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk.

dc.type

Journal article

duke.contributor.orcid

Alexander, John H|0000-0002-1444-2462

duke.contributor.orcid

Pencina, Michael J|0000-0001-5798-8855|0000-0002-1968-2641

pubs.begin-page

39

pubs.issue

1

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School of Medicine

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Duke Clinical Research Institute

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Biostatistics & Bioinformatics

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Duke

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Institutes and Centers

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Basic Science Departments

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Medicine, Cardiology

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Medicine

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Clinical Science Departments

pubs.publication-status

Published

pubs.volume

17

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