CARMELINA: New linagliptin analyses demonstrate CV, kidney safety across all age, renal impairment groups

SAN FRANCISCO — In adults with type 2 diabetes, established cardiovascular disease and renal impairment, the DPP-IV inhibitor linagliptin did not increase risk for a new CV event or progression of renal disease when compared with placebo, regardless of age or the level of renal impairment, according to new findings from the CARMELINA trial presented at the American Diabetes Association Scientific Sessions.

The new CARMELINA subanalyses, presented for the first time Tuesday, demonstrate that linagliptin (Tradjenta, Boehringer Ingelheim/Eli Lilly) is safe in a broad population of high-risk patients with type 2 diabetes, suggesting the drug is an option for patients who are at particularly high risk for hypoglycemia, according to researchers.

“We think that we provide additional evidence to aid in the decisionmaking process for selecting medications, especially in this population,” Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City and clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas, said during a press conference Monday. “We demonstrated safety in terms of cardiovascular events and safety in terms of renal progression. This is important because linagliptin is the one DPP-IV inhibitor that is not excreted in the kidneys. It does not need a dose adjustment and it can be given irrespective of renal function."

“These are patients every doctor is seeing in clinical practice on a daily basis,” Rosenstock said. “They’re very difficult to [manage] because there are a limited number of drugs that can be given.”

No increased risk

Rosenstock and colleagues analyzed data from 6,979 adults with type 2 diabetes with a history of vascular disease and a urinary albumin to creatinine ratio of at least 200 mg/g, recruited from 605 sites in 27 countries between 2013 and 2016 (mean age, 66 years; mean diabetes duration, 14.8 years). Participants spanned a broad range of kidney function; CARMELINA had the highest proportion of individuals with reduced kidney function compared with other DPP-IV inhibitor CV outcomes trials conducted to date, according to researchers.

Researchers randomly assigned participants to 5 mg linagliptin once daily (n=3494) or placebo once daily (n=3485) added to usual care for a median of 2.2 years. Other glucose-lowering medications or insulin could be added based on clinical need. Primary outcome measure of the study was the time to first occurrence of a composite of CV death, nonfatal myocardial infarction or nonfatal stroke. Researchers also assessed incidence of end-stage renal disease, or a sustained decrease of 40% or more in estimated glomerular filtration rate.

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Researchers found that participants in the linagliptin group experienced CV outcomes at a rate comparable to participants in the placebo group, indicating linagliptin did not have a negative effect on CV risk. Incidence of MI, stroke or CV death was similar between the linagliptin and placebo groups (12.4% vs. 12.1%), for an HR of 1.02 (95% CI, 0.89-1.17). Researchers observed no between-group difference for hospitalization for heart failure or severe renal events.

In subanalyses assessing time to first occurrence of the individual CV endpoints, researchers observed no increased risk in the linagliptin group vs. placebo across all age groups and all levels of kidney function, Mark E. Cooper, AO, MBBS, PhD, FRACP, head of the diabetes department in the Central Clinical School at Monash University in Melbourne, Australia, said during the press conference.

Key renal outcomes in the two treatment groups were also comparable, according to researchers, with 9.4% of participants in the linagliptin group and 8.8% of participants in the placebo group experiencing a secondary renal outcome, for an HR of 1.04 (95% CI, 0.89-1.22). In subanalyses, findings again persisted across all age groups and kidney function groups, Cooper said.

“We know there is a very close relationship between age and increasing risk for heart failure and those patients with lower eGFR tend to have a higher risk for heart failure, so it was important to determine if this effect of neutrality was seen in these subgroups,” Cooper said.

Managing hypoglycemia

As Endocrine Today previously reported, the mean between-group difference in HbA1c was 0.36% at 2.2 years, with the effects observed across renal function groups and age groups. 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, 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 findings in October.

"This data is particularly important because it proves 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 said in a press release announcing the findings. “These are patients that nearly every provider sees in his or her clinical practice on a daily basis and are difficult to treat because of risk of hypoglycemia, which was not increased with linagliptin, and these patients had better glucose control.” – by Regina Schaffer

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Reference:

Rosenstock J, et al. CREDENCE AND CARMELINA — results from two major clinical trials in kidney and cardiovascular disease in diabetes. Presented at: American Diabetes Association 79th Scientific Sessions; June 7-11, 2019 San Francisco.

Disclosures: Rosenstock reports he has received research and other financial support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Bukwang, Eli Lilly, Genentech, GlaxoSmithKline, Intarcia, Janssen, Lexicon, Melior Pharmaceuticals, Merck, Novo Nordisk, Oramed, PegBio Co., Pfizer and Sanofi.