Study finds noninferior cardiovascular safety of linagliptin versus glimepiride in early diabetes

The dipeptidyl peptidase-4 inhibitor-linagliptin has demonstrated noninferiority in placebo-controlled cardiovascular safety trials however, its role in type 2 diabetes treatment had not been compared with other potential competitors. In a recent study published in the Journal of American Medical Association (JAMA), scientists have compared linagliptin with glimepiride where it has demonstrated noninferior cardiovascular safety effects when compared with cardiovascular safety effects of glimepiride, particularly in patients with early type 2 diabetes.

The scientists conducted a randomized noninferiority clinical trial that included 6033 participants followed up for a median of 6.3 years, the use of linagliptin compared with glimepiride added to usual care resulted in rates of the primary outcome (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) of 11.8% vs 12.0%.

Patients were randomized to receive 5 mg of linagliptin once daily or 1 to 4 mg of glimepiride once daily in addition to usual care. Investigators were encouraged to intensify glycemic treatment, primarily by adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to clinical need.

The primary outcome was time to the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride, defined by the upper limit of the 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3. Of 6042 participants randomized, 6033 (mean age, 64.0 years; 2414 [39.9%] women; mean glycated hemoglobin, 7.2%; median duration of diabetes, 6.3 years; 42% with the macrovascular disease; 59% had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years.

Key findings of the study

• The primary outcome occurred in 356 of 3023 participants in the linagliptin group and 362 of 3010 in the glimepiride group, meeting the non inferiority criterion but not superiority.


• Adverse events occurred in 93.4% of the participants in the linagliptin group and 94.9% in the glimepiride group, with 0.5% in the linagliptin group vs 0.5% in the glimepiride group with adjudicated-confirmed acute pancreatitis.


• At least 1 episode of hypoglycemic adverse events occurred in 10.6% participants in the linagliptin group and 37.7% in the glimepiride group.

The authors conclude "Among adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median 6.3 years resulted in a noninferior risk of a composite cardiovascular outcome."

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