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CARMELINA: Linagliptin safe, effective in type 2 diabetes with CVD, kidney disease
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Among adults with type 2 diabetes, established cardiovascular disease and/or chronic kidney disease, the DPP-IV inhibitor linagliptin demonstrated CV safety and a neutral effect for hospitalization for heart failure and kidney outcomes vs. placebo, according to findings from the CARMELINA trial presented at the European Association for the Study of Diabetes annual meeting .
“In CARMELINA, linagliptin [Tradjenta, Boehringer Ingelheim and Eli Lilly] demonstrated cardiovascular safety in a clinically relevant population of patients with type 2 diabetes, cardiovascular disease and chronic kidney disease,” Bernard Zinman, MD, professor in the department of medicine at the University of Toronto and senior scientist at the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital in Toronto, said during a presentation. “Linagliptin did not increase hospitalization for heart failure even in patients at high risk for heart failure. The overall safety profile, including kidney outcomes in this high-risk patient population, was reassuring.”
In presenting findings from CARMELINA, a randomized controlled CV outcomes trial enrolling 6,979 adults across 605 centers in 27 countries, the researchers noted the study met its primary endpoint of first occurrence of CV death, nonfatal myocardial infarction or nonfatal stroke in adults with type 2 diabetes and high CV risk, and also demonstrated an overall safety profile for linagliptin consistent with previous data. No new safety signals were observed.
Beginning in 2013, researchers randomly assigned participants to 5 mg once-daily linagliptin (n = 3,494; 61.5% men; mean age, 66 years) or placebo (n = 3,485; 64.3% men; mean age, 66 years) for a median of 2.2 years. Average HbA1c for the cohort was 8%, mean diabetes duration was 15 years, and more than half of participants were using insulin at baseline.
Renal outcomes included time to first occurrence of renal death, sustained end-stage renal disease or a sustained decrease in estimated glomerular filtration rate of at least 50%.
Within the cohort, CV events that contributed to the primary endpoint occurred in 434 adults (12.4%) in the linagliptin group and 420 adults (12.1%) in the placebo group. Renal events reflecting declining kidney function occurred in 327 adults (9.4%) in the linagliptin group and 306 adults (8.8%) in the placebo group.
Hospitalization for heart failure occurred in 209 adults (6%) in the linagliptin group and 226 adults (6.5%) in the placebo group.
At 2.2 years, the mean between-group difference in HbA1c was 0.36%, Steven E. Kahn, MB, ChB, professor of medicine at the VA Puget Sound Health Care System and University of Washington in Seattle, said during a presentation of the metabolic findings. Additionally, fewer patients required initiation of insulin or an increase in insulin dose in the linagliptin group vs. the placebo group (555 vs. 729, respectively; HR = 0.72; 95% CI, 0.65-0.81). There were no between-group differences for changes in body weight, lipids or blood pressure, Kahn said.
In introducing the study findings, Julio Rosenstock, MD, director of the Dallas Diabetes and Endocrine Center, noted that the CARMELINA steering committee decided to include renal endpoints in the trial, which were not required by the FDA, to address a need for more information in a high-risk patient population. In CARMELINA, 62.3% of enrolled participants had an eGFR less than 60 mL/min/1.73m² — more than double the number of participants with renal disease in the EXAMINE trial for alogliptin (Nesina, Takeda), and more than three times greater than the number of participants in the SAVOR-TIMI and TECOS CV outcomes trials, Rosenstock said.
“People with diabetes have two to three times increased cardiovascular risk, and that risk is even doubled in people with chronic kidney disease,” Rosenstock said during the presentation. “Despite that, it is interesting that patients with type 2 diabetes and kidney disease have been underrepresented in most of the cardiovascular outcomes trials.” – by Regina Schaffer
Reference:
Rosenstock J, et al. CARMELINA symposium. Presented at: European Association for the Study of Diabetes Annual Meeting; Oct. 1-5, 2018; Berlin.
For more information:
CARMELINA trial data. Available at: www.carmelinatrial.com.
Disclosures: Boehringer Ingelheim and Eli Lilly supported this study. Rosenstock reports he has served on scientific advisory boards and received honoraria or consultant fees from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Intarcia Therapeutics, Janssen, Novo Nordisk and Sanofi, and has received grants/research support from Asahi Kasei, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Hanmi, Intarcia Therapeutics, Janssen, Lexicon, Merck, Novo Nordisk, Pfizer, Sanofi and Takeda. Zinman reports he has received grant support from AstraZeneca, Boehringer Ingelheim and Novo Nordisk, and consultant fees from AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novo Nordisk and Sanofi-Aventis.
Perspective
Back to TopDebra L. Simmons, MD, MS, FACE, FACP
The way the researchers designed this trial is important. Instead of only looking at CV outcomes, they also looked at renal events as a main secondary outcome. People who have CKD have higher incidence of CVD; however, it’s common in our studies that we don’t typically include people who have CKD beyond relatively minimal renal impairment – a small amount of microalbuminuria or a higher estimated GFR. The researchers also adjudicated events, including heart failure and kidney outcomes. This study demonstrates that, with one agent, patients were able to take it safely without increased risk and less burden of other medications, including insulin, which is an important point. It also represents a growing interest in the communities of endocrinology, cardiology and nephrology about people who have diabetes with comorbid kidney disease and/or CVD. Why don’t we know more about these people? This trial was well designed to help answer that question.
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