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CARMELINA, CAROLINA shed new light on CV safety for linagliptin, glimepiride
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.
Additionally, a head-to-head comparison of the sulfonylurea glimepiride against linagliptin (Tradjenta, Boehringer Ingelheim/Eli Lilly) in a cohort of more than 6,000 adults with type 2 diabetes demonstrated no between-group differences for incidence of nonfatal myocardial infarction, nonfatal stroke and CV death during a median of 6 years, according to data from the CAROLINA trial.
“We think that we provide additional evidence to aid in the decision-making 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. “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.”
CARMELINA findings
For the CARMELINA trial, Rosenstockand 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 from 2013 to 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=3,494) or placebo once daily (n=3,485) 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 MI 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.
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 differences 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 a 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.
CAROLINA findings
In reporting findings from the CAROLINA trial — the first active-comparator CV outcomes study to evaluate two commonly used antidiabetes medications — researchers also observed a higher incidence of hypoglycemia and weight gain in the glimepiride group, adding that linagliptin has a “clinically relevant safety advantage” that should be considered along with its higher cost. Researchers, however, noted that the findings vindicate glimepiride from “an old cardiovascular stigma.”
“We take a lot of pride in this study,” Rosenstock said during a press conference. “We are addressing, in this trial, a lingering debate that has been going on for many years in terms of the safety of sulfonylureas.”
Rosenstock and colleagues analyzed data from 6,033 adults aged 40 to 85 years with type 2 diabetes, recruited from more than 600 sites in 43 countries from 2010 to 2018 (median diabetes duration, 6.2 years). Participants had established CVD or increased risk for CVD. Researchers randomly assigned participants to 5 mg linagliptin once daily (n = 3,023) or a daily dose of up to 4 mg glimepiride (n = 3,010), as add-on therapy in addition to any prescribed antidiabetes medications, for a median of 6.3 years. The follow-up period was the longest for a CV outcomes trial, according to the researchers. Primary outcome was a composite of CV death, nonfatal MI and nonfatal stroke.
Researchers determined there were no between-group differences between participants assigned to linagliptin or glimepiride with respect to CV events. The HR for the primary outcome was 0.98 (95% CI, 0.84-1.14). Corresponding HRs for CV mortality and non-CV mortality were 1 (95% CI, 0.81-1.24) and 0.82 (95% CI, 0.66-1.03), respectively. There was no between-group difference for HbA1c.
“We found no difference in cardiovascular events, heart failure or mortality risk between linagliptin and glimepiride,” Nikolaus Marx, MD, FESC, FAHA, professor of medicine/cardiology and head of internal medicine at Aachen University in Germany, said during the press conference. “This study resolves the decades-long, highly debated cardiovascular safety of sulfonylureas, especially glimepiride, beginning 50 years ago ... and now, with CAROLINA, showing a similar incidence of cardiovascular events.”
Increased hypoglycemia risk
Marx said participants in the glimepiride group in CAROLINA experienced modest weight gain vs. participants assigned linagliptin (between-group difference, –1.5 kg; 95% CI, –1.8 to –1.3) and greater incidence of investigator-reported hypoglycemia (37.7% vs. 10.6%), for an HR for hypoglycemia of 0.23 for linagliptin vs. glimepiride (95% CI, 0.21-0.26), or a number needed to treat of three over 6 years. Patients in the glimepiride group also experience more severe hypoglycemia vs. those assigned linagliptin (2.2% vs. 0.3%).
“Although we hypothesized in CAROLINA that we would potentially see differences in cardiovascular outcomes when we directly compared linagliptin and glimepiride, we saw none, and are now in position to provide a clear answer to vindicate sulfonylureas, at least glimepiride, from the old cardiovascular stigma,” Rosenstock said. – by Regina Schaffer
- References:
- Rosenstock J, et al. CREDENCE and CARMELINA — results from two major clinical trials in kidney and cardiovascular disease in diabetes.
- Rosenstock J, et al. The CAROLINA trial — first results of the cardiovascular outcomes trial comparing linagliptin vs. glimepiride.
Disclosures: Marx reports he has served on advisory panels and received research support or speaking fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly Diabetes, Merck, Novo Nordisk and Sanofi. 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.