The CARMELINA trial demonstrated noninferiority of linagliptin compared with placebo in CV events in high risk people with type 2 diabetes.
Many trials have talked about the CV safety of using selective DPP-4 inhibitors for people with type 2 diabetes, but have not examined the effect for people who have type 2 diabetes along with a high cardiovascular risk and chronic kidney disease. According to the American Heart Association, adults with diabetes are at two to four times higher risk to die from cardiovascular disease than adults without diabetes. The CDC also estimates that 38% of the reported cases of end-stage kidney disease are caused by diabetes. This indicates that since diabetes is a major risk factor for both CV disease and kidney disease, studies need to be conducted to evaluate the effects of the glucose-lowering medications on CV and kidney outcomes in patients at high risk.
The CARMELINA trial, “Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults with Type 2 Diabetes and High Cardiovascular and Renal Risk,” was presented at the 79th ADA scientific sessions to reveal the effect of linagliptin, a selective DPP4-inhibitor in people with type 2 diabetes at high cardiorenal risk.
This trial was a randomized noninferiority, double-blind, placebo-controlled, multi-center clinical trial where participants were randomized to either receive linagliptin 5mg daily (n=3494) or placebo (3485) added to the participants’ usual care. Inclusion criteria required the participants to be adults with type 2 diabetes, A1C values of 6.5% to 10%, and at a high CV risk (history of coronary artery disease, stroke or peripheral vascular disease, and micro- or macro-albuminuria) and renal risk (eGFR of 45-75mL/min/1.732 and urine albumin-to-creatinine ratio ³200mg/g, or eGFR of 15-45 mL/min/1.732 regardless of urine albumin-to-creatinine ratio). Primary outcome of the study was time to first occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained decrease of at least 40% in eGFR from baseline. A decrease of at least 50% in eGFR was considered a tertiary outcome.
57% of the participants had established CV disease, 74% had prevalent kidney disease, 33% had both CV and kidney disease, and 15.2% had eGFR<30mL/min/1.732. No significant differences in baseline characteristics between groups were present and the median observation time of the study was 2.2 years.
The primary outcome occurred in 12.4% of participants in the linagliptin group (5.77 per 100 person-years) and 12.1% in the placebo group (5.63 per 100 person-years), absolute incidence rate difference of 0.13 (95% CI, -0.63 to 0.90) per 100 person-years (HR, 1.02; 95% CI, 0.89-1.17; P<0.001) confirming noninferiority, and superiority testing was not statistically significant.
The risk of the secondary outcome was also not statistically significant between both groups, and the test for superiority was also not statistically significant. There was no significant difference between groups in the incidence of death due to any cause, hospitalization for heart failure, composite of sustained ESRD, death due to renal failure, and ³50% decrease in eGFR. Linagliptin resulted in small A1C reductions without an increase in hypoglycemia in the participants of the study. As mentioned in the study, this finding is noteworthy especially because only a few glucose-lowering medications have been studied in patients with advanced chronic kidney disease.
The frequency of malignancies was 3.3% in the linagliptin group and 3.8% in the placebo group. Pancreatic cancers were rare but the frequency in the linagliptin group was slightly higher (0.3% vs 0.1%) and the oncology expert assessment committee reported 1 case to be possibly related to the treatment.
In a nutshell, the findings of this study, involving people with type 2 diabetes and high cardiorenal risk, demonstrated linagliptin compared with placebo, did not show evidence of CV benefit and there was no difference between the groups in the incidence of the secondary kidney outcome, with modest A1C reductions in linagliptin group without an increase in hypoglycemia.
- The CARMELINA trial is a significant study that differs from other DDP-4 inhibitor trials as it evaluates the effect of linagliptin on CV and kidney outcomes in people with type 2 diabetes at high risk of cardiorenal events.
- The study findings demonstrated noninferiority of linagliptin compared with placebo over a median of 2.2 years in terms of CV events and incidence of the secondary kidney composite outcome.
- The use of linagliptin added to usual care resulted in modest A1C reductions with no significant increase in hypoglycemia.
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. JAMA. 2019;321(1):69-79. doi:10.1001/jama.2018.18269
American Heart Association. Cardiovascular Disease and Diabetes. https://www.heart.org/en/health-topics/diabetes/why-diabetes-matters/cardiovascular-disease–diabetes
Centers for Disease Control and Prevention. Chronic Kidney Disease in the United States, 2019. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2019. https://www.cdc.gov/kidneydisease/publications-resources/2019-national-facts.html.
Marian Ayad, BPharm, PharmD candidate, University of Colorado Skaggs School of Pharmacy