American Diabetes Association Scientific Sessions
American Diabetes Association Scientific Sessions
June 11, 2019
3 min read

CAROLINA: Active-comparator study ‘vindicates’ glimepiride for CV safety

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SAN FRANCISCO — A head-to-head comparison of the sulfonylurea glimepiride against the DPP-IV inhibitor linagliptin 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 cardiovascular death during a median of 6 years, according to data from the CAROLINA trial presented at the American Diabetes Association Scientific Sessions.

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 (Tradjenta, Boehringer Ingelheim/Eli Lilly) 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,” 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 are addressing, in this trial, a lingering debate that has been going on for many years in terms of the safety of sulfonylureas.”

‘Lingering concern’

Sulfonylureas, which work by increasing insulin secretion, have been available for more than 60 years, provide good glycemic response for patients and are low cost, Rosenstock said. The therapy, however, has limitations, including increased risk for hypoglycemia, weight gain and limited glycemic durability over time, as well as a “lingering concern” regarding the class’ long-term CV safety dating back to research conducted in the 1960s.

“In CAROLINA, we wanted to test this question using a current-generation sulfonylurea, and we found that glimepiride does not increase cardiovascular risk relative to linagliptin,” Rosenstock said. “This is reassuring, as many patients are currently prescribed glimepiride.”

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 between 2010 and 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.


“For all of these cardiovascular outcomes trials, the comparator has been placebo,” Rosenstock said. “Not a single one has been [conducted] with an active comparator.”

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 experienced modest weight gain vs. participants assigned linagliptin (between-group difference, –1.5 kg; 95% CI, –1.8 to –1.3) and experienced 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 in a press release announcing the findings. “However, with a significantly higher risk of hypoglycemia and a modest, but statistically significant, weight gain with glimepiride compared with linagliptin, results from the CAROLINA trial confirm an important, clinically relevant safety advantage of linagliptin over glimepiride that should be considered in the decision-making process for selecting therapy in addition to cost considerations.” – by Regina Schaffer


Rosenstock J, et al. The CAROLINA trial — first results of the cardiovascular outcomes trial comparing linagliptin vs. glimepiride. Presented at: American Diabetes Association 79th Scientific Sessions; June 7-11, 2019; San Francisco.

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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.