Conference Coverage

CAROLINA findings reaffirm linagliptin’s safety, free glimepiride of CV-risk stigma



– The sulfonylurea glimepiride (Amaryl) did not increase the risk of cardiovascular events in patients with type 2 diabetes and cardiovascular risk in a head-to-head comparison with the dipeptidyl peptidase–4 (DPP-4) inhibitor linagliptin (Tradjenta), a drug with proven cardiovascular safety, according to findings from the CAROLINA study presented at the scientific sessions of the American Diabetes Association.

Dr. Julio Rosenstock

Linagliptin’s cardiovascular safety, compared with placebo, was demonstrated in the CARMELINA study (JAMA. 2019;321[1]:69-79), but CAROLINA pitted the DPP-4 inhibitor against an active comparator, glimepiride, which along with other sulfonylureas, carries a warning for increased risk of cardiovascular mortality. The latest findings about the comparator were not expected, but seem to set aside the lingering doubts about cardiovascular safety in at least the modern-day sulfonylureas.

“The stigma that sulfonylureas have had for more than 50 years” has been lifted. “We take a lot of pride in this study,” said principal investigator and endocrinologist Julio Rosenstock, MD, a clinical professor of medicine at the University of Texas Southwestern Medical Center, Dallas.

In 1970, the University Group Diabetes Program trial reported 26 cardiovascular deaths in 204 patients who received with tolbutamide – a first-generation sulfonylurea no longer in common use – compared with 10 deaths in 205 patients who received placebo (Diabetes. 1970;19[Suppl]:789-830). The finding led to a warning of increased risk of cardiovascular mortality that still appears on sulfonylurea labels today.

The results were never confirmed by subsequent studies, and debate about the cardiovascular safety of sulfonylureas continued, with many physicians over the years calling for a large, rigorous trial to resolve the issue once and for all.

Dr. Nikolau Marx

]And that’s what the CAROLINA findings delivered – a resolution to the “decades-long debate” about cardiovascular safety with glimepiride and likely other modern sulfonylureas, according to coinvestigator and cardiologist Nikolaus Marx, MD, a professor of medicine at Aachen (Germany) University.

The CAROLINA investigators randomized 1:1 more than 6,000 patients with type 2 diabetes at 607 sites in 43 countries to receive either linagliptin 5 mg daily or glimepiride 1-4 mg daily on a background therapy, in most cases, of metformin. The median diabetes duration was 6.3 years, and baseline hemoglobin A1c was 7.15%. In all, 42% of the patients had established cardiovascular disease, and 37% had two or more risk factors that were managed by standard care.

After a median follow-up of 6.3 years, there was no difference between linagliptin and glimepiride in the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (11.8% and 12%, respectively; P = .76), nor were there any differences in the individual components. Likewise, there were no differences between the two drugs in hospitalization for heart failure (3.7% and 3.1%, P = .18) or all-cause mortality (10.2% and 11.2%; P = .23), and no difference in glucose control – a drop of about 0.3% in the HbA1c level at 1 year, then a slow creep back to baseline at around 4 years.

“We believe cardiovascular safety should no longer be a consideration in [deciding] between these two agents,” said Dr. Rosenstock, who cochaired the session with Dr. Marx.

However, there was a modest weight gain with glimepiride, and a marked increase in the risk of moderate to severe hypoglycemia, compared with linagliptin (30.9% and 6.5%, respectively; P less than .0001). Both weight gain and hypoglycemia are recognized side effects of sulfonylureas.

Sulfonylureas are far less expensive than the DPP-4 inhibitors are, so “other than cost consideration ... [the findings] support use of DPP-4 inhibitors before sulfonylureas if hypoglycemia and weight gain are also considerations,” Dr. Rosenstock said.

Robert H. Eckel, MD, an endocrinologist, said he has been “taking people off sulfonylureas for years because I [wasn’t] sure they were safe. This study has helped me know that I can continue [them] safely.”

Dr. Robert Eckel is a professor of medicine at the University of Colorado, Aurora. M. Alexander Otto/MDedge News

Dr. Robert Eckel

However, even with the new data, “the only reason I would [use a sulfonylurea] is cost. Cost is the bottom line in the clinic,” added Dr. Eckel, a professor of medicine at the University of Colorado, Aurora.

The trial findings pose no challenge to current guidelines for type 2 diabetes and the recommendation to opt first for a second-line medication with proven cardiovascular benefit, such as a sodium-glucose transporter 2 inhibitor or glucagonlike peptide–1 receptor agonist, in at-risk patients.

Boehringer Ingelheim, the maker of linagliptin, funded the study in collaboration with comarketer, Eli Lilly. Dr. Rosenstock and Dr. Marx disclosed numerous ties to Boehringer Ingelheim and Eli Lilly, and other companies not associated with the study. Dr. Eckel disclosed ties with companies not associated with the study.

SOURCE: Rosenstock J et al. ADA 2019.

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