Linagliptin and Glimepiride Have Comparable Cardiovascular Safety Effects in Type 2 Diabetes at High Cardiovascular Risk

Results of CAROLINA trial, a multi-center, international clinical trial of more than 6,000 adults and the longest-running study dedicated to cardiovascular outcomes in people with type 2 diabetes, presented at ADA’s Scientific Sessions

Results of CAROLINA trial, a multi-center, international clinical trial of more than 6,000 adults and the longest-running study dedicated to cardiovascular outcomes in people with type 2 diabetes, presented at ADA’s Scientific Sessions

SAN FRANCISCO, June 10, 2019 /PRNewswire/ -- The diabetes medications glimepiride and linagliptin had similar impacts on cardiovascular morbidity and mortality for a median period of 6.3 years, when added to standard care for people with relatively early type 2 diabetes (T2D), many of whom had an elevated risk of cardiovascular disease (CVD) or existing CVD at the beginning of the study, according to research presented today at the American Diabetes Association‘s® (ADA’s) 79th Scientific Sessions® at the Moscone Convention Center in San Francisco. The study was featured today at “The CAROLINA Trial—First Results of the Cardiovascular Outcomes Trial Comparing Linagliptin vs. Glimepiride” symposium.

(PRNewsFoto/American Diabetes Association)

CVD is a major risk for and the leading cause of death for people living with T2D, and since 2008, the FDA requires diabetes medications to demonstrate cardiovascular (CV) safety. Many CV outcomes studies have been conducted on diabetes medications in a setting that compared a medication to a placebo. The CAROLINA trial, however, was the only active-comparator study so far that evaluated and compared two commonly used diabetes medications. The trial evaluated and compared the effects of linagliptin, a DPP-4 inhibitor, and glimepiride, which is in the class of sulfonylurea (SU) medications, on CV morbidity and mortality in patients with T2D. Although linagliptin and glimepiride work differently, they both lower glucose levels by stimulating the body’s insulin production. In this double-blind, randomized trial, participants were assigned to receive one of the two medications to determine which medication was better suited as add-on therapy to metformin or other medications used in patients. Researchers then analyzed if there was evidence of superiority in terms of the occurrence of CV events, as an add-on therapy to metformin or other diabetes medications used by study participants.

The CAROLINA trial was an international study conducted from 2010 to 2018 of 6,033 adults with T2D from more than 600 sites across 43 countries. The participants ranged in age from 40 to 85 years, had a median disease duration of 6.2 years, and all had either an increased risk of CVD or established CVD. Participants were randomly assigned to receive either 5mg, once daily, of linagliptin, or a daily dose of up to 4mg of glimepiride. The participants took the medication in addition to their usual diabetes medications.

The results announced today reflect a median 6.3 years of follow-up, the longest follow-up period ever for a CV outcomes trial in diabetes. Researchers determined that there were no significant differences between linagliptin and glimepiride in their effect on CV events, however, there was a significantly higher risk of hypoglycemia and a modest weight gain for the participants in the glimepiride group.

“Since the publication of the University Group Diabetes Program trial in the 1960s indicating that a first-generation sulfonylurea increased the risk for cardiovascular mortality, the scientific community and public health regulators have asked themselves if sulfonylureas are cardiovascular-safe,” said Nikolaus Marx, MD, FESC, FAHA, professor of medicine/cardiology and head of internal medicine at Aachen University in Aachen, Germany. “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. This is reassuring, as many patients are currently prescribed glimepiride.”

Specifically, the hazard ratio (HR) and 95% confidence interval (CI) for the primary outcome—a composite of CV death, non-fatal myocardial infarction (MI), non-fatal stroke (3P-MACE)—between the 3,023 participants receiving linagliptin and 3,010 receiving glimepiride, was 0.98 (0.84, 1.14), while the corresponding HR (95% CI) for CV mortality and non-CV mortality were 1.00 (0.81, 1.24) and 0.82 (0.66, 1.03). There was no overall difference between the treatment groups in HbA1c, while an average between-group difference in weight of –1.5 kg (95% CI –1.8, –1.3) was seen favoring linagliptin. Of the participants, 10.6% vs. 37.7% had ≥ 1 investigator-reported episode of hypoglycemia, yielding a HR for hypoglycemia of 0.23 (0.21, 0.26) for linagliptin vs. glimepiride. This translated to a number needed to treat (NNT) of three over six years, to prevent one episode of hypoglycemia. The same magnitude of relative reduction in risk for hypoglycemia was observed across all severity categories of hypoglycemia, e.g., severe hypoglycemia (as defined by the study as a hypoglycemic event requiring the assistance of another person to administer carbohydrate, glucagon or other resuscitative actions) that affected 0.3% vs. 2.2% of participants, providing a HR of 0.15 (0.08, 0.29), and corresponding NNT of 45.

“In the context of the established cardiovascular safety profile of linagliptin versus placebo, convincingly demonstrated in the CARMELINA trial, this comparative trial was in position to fully address the decades-long, unresolved and highly debated, cardiovascular mortality controversy for sulfonylureas,” said trial principal investigator 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, Texas. “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. 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.”

To speak with Dr. Marx or Dr. Rosenstock, please contact the ADA Press Office on-site at the Moscone Convention Center on June 7-11, by phone at 415-978-3606 or by email at

The American Diabetes Association’s 79th Scientific Sessions, the world’s largest scientific meeting focused on diabetes research, prevention and care, is held June 7-11, 2019, at the Moscone Center in San Francisco, California. Nearly 15,000 leading physicians, scientists, health care professionals and industry representatives from around the world are expected to convene at the Scientific Sessions to unveil cutting-edge research, treatment recommendations and advances toward a cure for diabetes. During the five-day meeting, attendees receive exclusive access to more than 850 presentations and 2,000 original research presentations, participate in provocative and engaging exchanges with leading diabetes experts, and earn Continuing Medical Education (CME) or Continuing Education (CE) credits for educational sessions. The program is grouped into eight thematic areas: Acute and Chronic Complications; Behavioral Medicine, Clinical Nutrition, Education and Exercise; Clinical Diabetes/Therapeutics; Epidemiology/Genetics; Immunology/Transplantation; Insulin Action/Molecular Metabolism; Integrated Physiology/Obesity; and Islet Biology/Insulin Secretion. Gretchen Youssef, MS, RDN, CDE, President of Health Care and Education, delivered her address, “It’s All about Access!,” on Saturday, June 8, and Louis H. Philipson, MD, PhD, FACP, President of Medicine and Science, delivered his lecture, “Precision Medicine—Addressing the Many Faces of Diabetes,” on Sunday, June 9. Join the Scientific Sessions conversation on social media using #ADA2019.

About the American Diabetes Association
Every day more than 4,000 people are newly diagnosed with diabetes in America. Nearly 115 million Americans have diabetes or prediabetes and are striving to manage their lives while living with the disease. The American Diabetes Association (ADA) is the nation’s leading voluntary health organization fighting to bend the curve on the diabetes epidemic and help people living with diabetes thrive. For nearly 80 years the ADA has been driving discovery and research to treat, manage and prevent diabetes, while working relentlessly for a cure. We help people with diabetes thrive by fighting for their rights and developing programs, advocacy and education designed to improve their quality of life. Diabetes has brought us together. What we do next will make us Connected for Life. To learn more or to get involved, visit us at or call 1-800-DIABETES (1-800-342-2383). Information is available in English and Spanish. Join the fight with us on Facebook (American Diabetes Association), Twitter (@AmDiabetesAssn) and Instagram (@AmDiabetesAssn).

Michelle Kirkwood
(703) 299-2053

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SOURCE American Diabetes Association