ADA 2019--Linagliptin, the DPP-4 inhibitor, showed similar risk for first or recurrent CV events or hopspitalization vs placebo in T2DM patients with high cardiorenal risk in CARMELINA subanalysis.
SAN FRANCISCO-Linagliptin (Tradjenta®) is comparable to placebo in cardiovascular (CV) and renal safety in patients with type 2 diabetes (T2DM) and kidney disease, according to new data from the CARMELINA clinical trial presented at the American Diabetes Association (ADA) Scientific Sessions meeting in San Diego, CA, June 7-11.
The primary results of the CARMELINA (The Cardiovascular and Renal Microvascular Outcome Study with Linagliptin) clinical trial, published earlier in the year, had demonstrated no increased risk for cardiovascular (CV) events, heart failure, or adverse kidney outcomes in patients with T2DM at high cardiorenal risk1 who took the dipeptidyl peptidase-4 inhibitor. The primary outcome measure in that study was time to first occurrence of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke (3-point major adverse CV event [MACE]).
The analysis presented here2 expanded inquiry into effects of linagliptin on global burden of CV disease as well as hospitalization in this population by comparing effects of linagliptin vs placebo on all plus first recurrent CV events and hospitalizations for any cause.
Prior to the presentation, Darren McGuire, MD, MHSc, the CARMELNA study co-chair and Distinguished Teaching Professor at the University of Texas Southwestern Medical Center, Dallas, TX, discussed the new report with ADAMeetingNews,org.
“The presentation at the Scientific Sessions will provide further updates of results from this first large and dedicated cardiorenal outcome trial in people with type 2 diabetes, including further analysis of effects in the more vulnerable participants, ie, those with the poorest renal function and the elderly,” McGuire said.
Linagliptin safety confirmed
CARMELINA enrolled 6979 patients with a mean age of 65.9 years; of those 26.8% had a history of heart failure and 58.5% had a history of ischemic heart disease. Median follow up was 2.2 years. The addition of recurrent events increased the number of 3-P MACE events for analysis in the linagliptin group from 434 to 530 and in the placebo group from 420 to 535. There were 1,157 all-cause first event hospitalizations which increased to 2,459 with recurrences in the linagliptin group and 1,213 first hospitalizations which increased to 2,459 recurrences in the group receiving placebo.
The investigators reported that across the 3-P MACE, the individual events, and the all-cause hospitalization, the range of the calculated relative risk compared to placebo was 0.89 to 1.04.
“Linagliptin showed similar risk for either first or recurrent cardiovascular or hospitalization events compared with placebo in patients with T2DM and cardiorenal disease, thus supporting the CV safety of linagliptin,” related lead author Nikolaus Marx, MD, Directorate, Section Head, Senior Physicians, Department of Cardiology, Angiology and Intensive Care Medicine, University Medical Center Aachen, Aachen, Germany.
From Clinical Trial to Real-World
A 5-year post-marketing monitoring program of linagliptin with comparators was described as a real-world study to complement the CARMELINA trial data, by presenter Chandrasekar Gopalakrishnan, MD, MPh, Senior Research Specialist, Department of Medicine, Division of Pharmacoepidemiology and Pharmacoeconmics, Brigham & Women’s Hospital, Boston, MA.
“There are limited real world data on the cardiovascular safety and effectiveness of linagliptin,” Gopalakrishnan indicated. “We aimed to evaluate the safety of linagliptin vs other glucose-lowering medications in a multiyear monitoring program using insurance claims data.”
The investigators identified 1:1 matching cohorts of T2DM patients who had either initiated linagliptin or other DPP-4 inhibitor (n=39,834 pairs), pioglitazone (Actos; n=29,646 pairs), or sulfonylureas (n=25,285 pairs).3 The primary outcome was a composite of hospitalization for myocardial infarction, stroke, unstable angina, or coronary revascularization. The mean follow-up was 0.8 years.
Linagliptin was found to have a similar risk of the composite outcome compared to other DPP-4 inhibitors (HR=0.90, 95% CI 0.8-1.02) and to pioglitazone (HR=0.99, CI 0.86-1.13), but was associated with reduced risk compared to sulfonylureas (HR=0.77, CI 0.66-0.90).
Gopalakrishnan noted that there was substantial uncertainty with their initial results, with wide confidence intervals subject to misinterpretation.
“However, with the accrual of additional data, precision increased,” he indicated, and the results were robust across numerous sensitivity analyses.
“These real-word data show that linagliptin has reassuring effectiveness and safety on a cCV outcome compared to other DPP-4s and pioglitazone, and is associated with a decreased risk compared to sulfonylureas,” he concluded.
1. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with Type 2 diabetes and high cardiovascular and renal risk. The CARMELINA randomized clinical trial. JAMA. 2019;321:69-79.
2. Marx N, McGuire DK, Johansen OE, et al. Analysis of first plus recurrent cardiovascular and hospitalization events in the cardiovascular and renal microvascular outcome study with linagliptin (CARMELINA) in patients with Type 2 diabetes and cardiorenal disease. Paper presented at the American Diabetes Association 79th Scientific Sessions; June 7-11, 2019; San Francisco, CA, Abstract 432.-P.
3. Patorno E, Gopalakrishnan C, Mahesri M, et al. Comparative cardiovascular safety and effectiveness of linagliptin in routine care: Final results from a 5-year post-marketing monitoring program. Paper presented at the American Diabetes Association 79th Scientific Sessions; June 7-11, 2019; San Francisco, CA, Abstract 1459-P.