linagliptin Safe for Diabetes Patients with Elevated Cardiovascular Risk


Among adults with recently-diagnosed type 2 diabetes and elevated cardiovascular risk, the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin and the sulfonylurea glimepiride treatment resulted in similar cardiovascular outcomes over a median 6.3 years.

Diabetes heart disease

Diabetes heart disease (©AdobeStock_AlexilusMedical)

Among adults with recently-diagnosed type 2 diabetes and elevated cardiovascular risk, the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin and the sulfonylurea glimepiride treatment resulted in similar cardiovascular outcomes over a median 6.3 years.

Both DPP-4 inhibitors and sulfonylureas are widely used second-line glucose-lowering agents. Findings from the Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes (CAROLINA) should help alleviate the long-held concern about cardiovascular safety of the sulfonylurea class, which dates back to a 50-year-old study conducted with an older-generation sulfonylurea agent.

CAROLINA was published September 19 in JAMA. The findings were first presented at the annual Scientific Sessions of the American Diabetes Association in June 2019, and again at the annual meeting of the European Association for the Study of Diabetes simultaneously with the publication. It is the first head-to-head trial comparing long-term effects of the two drug classes on cardiovascular morbidity and mortality in type 2 diabetes.

“The current study demonstrates noninferior cardiovascular safety effects for linagliptin vs glimepiride when used predominantly as a second-line glucose-lowering treatment option after metformin,” Julio Rosenstock, MD and colleagues wrote. 

However, the authors add that because linagliptin is associated with less weight gain and hypoglycemia than glimepiride, it is the preferred drug of the two to add when metformin alone isn’t sufficient to achieve hemoglobin A1c targets. On the other hand, the sulfonylurea is much less expensive.

In addition, Rosenstock and colleagues pointed out, neither drug provides a cardiovascular advantage, as do some of the sodium glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1)-receptor agonists.

In an accompanying editorial, Deborah J.Wexler, MD, Diabetes Center, Massachusetts General Hospital, Harvard Medical School, Boston, wrote that the findings suggest “clinicians can continue to use low-cost sulfonylureas added to metformin for management of hyperglycemia in type 2 diabetes with confidence in their effectiveness for reduction of microvascular complications as well as their cardiovascular safety. The adverse effect profile of sulfonylureas and their very low cost must be balanced against characteristics of other glucose-lowering medications as clinicians consider the best approach for an individual patient.”


The randomized, double-blind, active-controlled, noninferiority trial included 6033 adults with type 2 diabetes with hemoglobin A1c levels 6.5 to 8.5 percent, and were at elevated cardiovascular risk, defined as having documented atherosclerotic cardiovascular disease and cardiovascular risk factors.

They were randomized to receive 5mg / day of linagliptin or 1-4 mg / day of glimepiride in addition to other medications (most were taking metformin) and usual care. Investigators could add other glucose-lowering agents based on need.

In a median follow-up time of 6.3 years in both groups, the primary outcome― time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or nonfatal stroke―occurred in 11.8 percent of those given linagliptin versus 12.0 percent of the glimepiride group, a nonsignificant difference with hazard ratio 0.98 and P less than 0.001 for non-inferiority.

The glimepiride group gained approximately 1.54kg more of body weight than did the linagliptin group. Hypoglycemia was more common with glimepiride, with rates of moderate or severe hypoglycemic events occurring in 8.4 versus 1.4 per 100 participant years (hazard ratio 0.18, P less than 0.001). 

In her editorial, Wexler notes that further evidence on the comparative effectiveness of glimepiride and a DPP-4 inhibitor, a GLP-1 receptor agonist, and basal insulin, each added to metformin, is expected with the publication of her group’s Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study, in 2022.


Julio Rosenstock, MD; Steven E. Kahn, MB, ChB; Odd Erik Johansen, MD, PhD; et al. “Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial.” JAMA. doi:10.1001/jama.2019.13772 Published online September 19, 2019.

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