Comparative Cardiovascular Safety of Linagliptin vs Other Glucose-Lowering Drugs

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Linagliptin has similar cardiovascular safety to that of other agents in the dipeptidyl peptidase-4 inhibitor class and pioglitazone.

Linagliptin has similar cardiovascular (CV) safety to that of other agents in the dipeptidyl peptidase-4 (DPP-4) inhibitor class and pioglitazone, according to study results published in the Diabetes, Obesity and Metabolism. Furthermore, linagliptin was associated with a 24% decreased CV risk compared with sulfonylureas.

Linagliptin was approved in the United States in May 2011 for use in adults with type 2 diabetes. To assess the CV safety of linagliptin, the researchers used data from a prespecified sequential monitoring program from May 2011 to December 2015. While the program comprised 7 prespecified analyses, each based on 6-month data, the investigators reported the first 4 years of data in this study.

The goal was to compare the CV safety of linagliptin vs other glucose-lowering medications, including other DPP-4 inhibitors (alogliptin, saxagliptin, or sitagliptin), pioglitazone, or second-generation sulfonylureas (glimepiride, glipizide, or glyburide). The primary outcome was defined as a composite CV outcome of hospitalization for acute myocardial infarction, ischemic or hemorrhagic stroke, unstable angina, or coronary revascularization.

The investigators identified 3 pairwise 1:1 propensity-matched cohorts: (1) patients receiving linagliptin or other DPP-4 inhibitors (31,492 pairs), (2) linagliptin or pioglitazone (23,316 pairs), and (3) linagliptin or sulfonylureas (19,731 pairs) between May 2011 and December 2015.

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The mean age of the cohort was 55 years, including about 20% of participants >65 years. Approximately 10% of the participants had a history of CV disease. Most patient characteristics after matching did not change over the course of the monitoring program.

The results showed that linagliptin had similar CV safety to that of other members of the DPP-4 inhibitor class; this was seen both in the first sequential analysis (data through June 2013) with 15.6 vs 19.6 events/1000 person-years (hazard ratio [HR], 0.80; 95% CI, 0.63-1.01) and the sixth sequential analysis (data through December 2015) with 16.2 vs 17.9 events/1000 person-years (HR, 0.91; 95% CI, 0.79-1.05).

The CV safety of linagliptin was also similar to that of pioglitazone, both in the first (17.87 vs 19.5 events/1000 person-years; HR, 0.94; 95% CI 0.71-1.26) and the sixth sequential analysis (16.3 vs 16.8 events/1000 person-years; HR, 0.98; 95% CI, 0.84-1.15).

However, treatment with linagliptin showed a reduced risk for CV outcomes compared with second-generation sulfonylureas, both in the first (12.3 vs 19.1 events/1000 person-years; HR, 0.66; 95% CI, 0.48-0.93) and the sixth sequential analysis (14.6 vs 18.7 events/1000 person-years; HR, 0.76; 95% CI, 0.64-0.92).

“This monitoring [program] demonstrates the value of routinely collected healthcare data in a framework of principled epidemiological analyses to monitor prospectively the effectiveness and safety of approved medical products,” wrote the researchers.

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Patorno E, Gopalakrishnan C, Brodovicz KG, et al. Cardiovascular safety of linagliptin compared with other oral glucose-lowering agents in patients with type 2 diabetes: A sequential monitoring programme in routine care [published online April 2, 2019]. Diabetes Obes Metab. doi:10.1111/dom.13735