CARMELINA: Linagliptin Safe in Diabetes Across Age, Renal Groups

Marlene Busko

June 19, 2019

SAN FRANCISCO — In patients with type 2 diabetes and either cardiovascular disease or impaired kidney function, the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (Tradjenta, Boehringer Ingelheim/Lilly) demonstrated cardiovascular safety, no increased risk of hospitalization for heart failure, and "reassuring" kidney safety including a reduction in albuminuria — across renal function and age groups — over 2.2 years.

These findings, from a closer look at the Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA) outcome trial of linagliptin, showed that safety of the agent can be extended to older patients and those with worse kidney function, researchers report.

They presented these findings during a press briefing and symposium last week at the American Diabetes Association (ADA) 2019 Scientific Sessions.

In a population that included older patients and those with severe chronic kidney disease (CKD), linagliptin "demonstrated a reassuring long-term cardiovascular and safety profile, with a reduction in the progression of albuminuria," no increase in hypoglycemia, and no need to adjust the dose, CARMELINA investigator Julio Rosenstock, MD, University of Texas Southwestern Medical Center, Dallas, summarized to the press.

These data are “particularly important” because they prove “categorically the cardiovascular and kidney safety of linagliptin in those with type 2 diabetes who are at a high cardiovascular risk when some degree of kidney disease is associated,” Rosenstock noted.

"These are patients that every practicing doctor [who treats patients with type 2 diabetes] sees...on a daily basis and are difficult to treat because of the risk of hypoglycemia," he explained.

"The take-home message for the practicing clinician," said press briefing moderator Robert H. Eckel, MD, University of Colorado Anschutz Medical Campus, is that CARMELINA showed linagliptin "looks like a good choice," especially for older patients with type 2 diabetes and more advanced kidney disease.

And there was almost a hint of even greater benefit in individuals who were older than 75 years, he noted to Medscape Medical News.

"It just makes us feel that linagliptin in populations that in the past we weren't certain about look okay," he added. "It would make me modify my prescribing patterns if I had a choice — if I wanted to use a DPP-4 inhibitor in those groups."

Main Findings Showed Cardiac and Renal Safety

The main results from CARMELINA were presented at the European Association for the Study of Diabetes (EASD) 2018 Annual Meeting in October, as reported by Medscape Medical News and published online in JAMA.

Among adults with type 2 diabetes at high risk of cardiovascular events (because of a history of MI or advanced coronary artery disease) and albuminuria, or they had impaired kidney function with or without albuminuria, linagliptin added to standard care did not increase the incidence of these events over a follow-up of 2.2 years.

Specifically, linagliptin was not inferior to placebo for the primary outcome of the 3-point major adverse cardiovascular events (MACE) and for a predefined secondary composite renal outcome. 

And, as published online in Circulation on November 11 and simultaneously presented at the American Heart Association (AHA) Scientific Sessions 2018, there was no increase in hospitalization for heart failure in patients treated with linagliptin in CARMELINA.

Older Patients, More CKD Than in Other DPP-4 Trials

The current analysis explored age and kidney function subgroups.

Compared with CARMELINA, other cardiovascular outcome trials of DPP-4 inhibitors enrolled a smaller percentage of patients who had prevalent kidney disease (eGFR < 60 mL/min/1.73m2) or were older, Rosenstock noted.

In CARMELINA, 62% of patients had prevalent kidney disease, compared with 28% of patients in the EXAMINE trial of alogliptin (Nesina, Takeda), 28% of patients in the SAVOR TIMI-53 study of saxagliptin (Onglyza, AstraZeneca), and 23% of patients in TECOS with sitagliptin (Januvia, Merck). 

More specifically, in CARMELINA, 15% of the patients had an eGFR of 15 to < 30 mL/min/1.73m2 (stage 4, severe CKD).

Another 28% had an eGFR of 30 to < 45 mL/min/1.73m2 (stage 3b, moderate CKD) and 19% of patients had an eGFR of 45 to < 60 mL/min/1.73m2 (stage 3a, moderate CKD) in CARMELINA.

Of the rest, 27% had an eGFR of 60 to < 90 mL/min/1.73m2 (stage 2, mild CKD) and 11% had an eGFR > 90 mL/min/1.73m2 (normal or high eGFR).

CARMELINA also included a higher percentage of patients over age 65 years (58% of patients) compared with SAVOR-TIMI (52%), TECOS (53%), and EXAMINE (35%).

And in CARMELINA, 17% of patients were age 75 years or older and 6% of patients were 80 years or older, although most were 65 to 75 years (40%) or younger than 65 years (43%).

Mark Cooper, MBBS, PhD, Monash University, Melbourne, Australia reported the trial results in these age and kidney function subgroups during the symposium at ADA.

CARMELINA randomized close to 7000 patients with type 2 diabetes and cardiovascular disease or CKD on standard therapy to receive linagliptin 5 mg/day (3404 patients) or placebo (3485 patients), he noted.

The trial was stopped when 611 individuals had a confirmed 3-point MACE (a large enough sample size to detect noninferiority), which occurred when patients had been followed for a median of 2.2 years.

No Significant Differences in Safety Outcomes in Subgroups

The current analysis found no significant difference in 3-point MACE among patients stratified by age or eGFR.

Importantly, there was no increase in 3-point MACE with linagliptin versus placebo in the oldest patients or those with the worst kidney function. 

Similarly, there was no increase in hospitalization for heart failure among patients who were < 65, 65-75, or > 75 years old, or among patients stratified into the four eGFR levels.

And linagliptin did not affect the risk of a ≥ 40% decline in eGFR.

Patients who received linagliptin versus placebo were more likely to excrete less albumin in their urine after 2.2 years.

The risk of hypoglycemia was highest among patients with the lowest eGFR, but this risk was the same in the placebo and linagliptin groups.

However, there was no increase in hypoglycemia with linagliptin versus placebo in patients in different age or kidney function subgroups.

"CARMELINA thus provides unique clinical evidence for a patient population that is highly relevant in clinical practice," Cooper said.

And in an ADA press release, he added: "These data will better inform clinicians about the choices of glucose-lowering therapies. The results also expand the evidence-base for individuals with reduced renal function at advanced age."

"It was particularly reassuring that the effects were consistent in individuals that were older than 75. Typically, elderly patients are not allowed to participate, yet this is the age group in which the incidence of type 2 diabetes is increasing most rapidly," he concluded.

ADA 2019 Scientific Sessions. Presented June 11, 2019.

This study was sponsored by Boehringer Ingelheim and Eli Lilly. Rosenstock had reported serving on scientific advisory boards and receiving honoraria or consulting fees from Eli Lilly, Sanofi, Novo Nordisk, Janssen, AstraZeneca, Boehringer Ingelheim, and Intarcia, and receiving grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Genentech, Janssen, Lexicon, Boehringer Ingelheim, and Intarcia. Cooper had reported receiving fees for advisory services to Boehringer Ingelheim.

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