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.
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.
Type
Journal articleSubject
CARMELINA® investigatorsKidney
Humans
Diabetic Nephropathies
Kidney Failure, Chronic
Cardiovascular Diseases
Diabetes Mellitus, Type 2
Disease Progression
Blood Glucose
Glomerular Filtration Rate
Treatment Outcome
Cause of Death
Risk Factors
Double-Blind Method
Research Design
Time Factors
Aged
Middle Aged
Female
Male
Renal Insufficiency, Chronic
Dipeptidyl-Peptidase IV Inhibitors
Biomarkers
Linagliptin
Glycated Hemoglobin A
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https://hdl.handle.net/10161/22865Published Version (Please cite this version)
10.1186/s12933-018-0682-3Publication Info
Rosenstock, Julio; Perkovic, Vlado; Alexander, John H; Cooper, Mark E; Marx, Nikolaus;
Pencina, Michael J; ... CARMELINA® investigators (2018). 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. Cardiovascular diabetology, 17(1). pp. 39. 10.1186/s12933-018-0682-3. Retrieved from https://hdl.handle.net/10161/22865.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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John Hunter Peel Alexander
Professor of Medicine
John H. Alexander, MD, MHS is a cardiologist and Professor of Medicine in the Department
of Medicine, Division of Cardiology at Duke University School of Medicine, as well
as the Vice Chief, Clinical Research in the Division of Cardiology. He is the Director
of Cardiovascular Research at the Duke Clinical Research Institute where he oversees
a large group of clinical research faculty and a broad portfolio of cardiovascular
clinical trials and observational clinical research programs. He is a
Michael J Pencina
Professor of Biostatistics & Bioinformatics
Michael J. Pencina, PhD Chief Data Scientist, Duke Health Vice Dean for Data Science
Director, Duke AI Health Professor, Biostatistics & Bioinformatics Duke University
School of Medicine
Michael J. Pencina, PhD, is Duke Health's chief data scientist and serves as vice
dean for data science, director of Duke AI Health, and professor of biostatistics
and bioinformatics at the Duke University School of Medicine. His work bridges the
fiel
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