• Diabetes Mellitus
• Myocardial Infarction
• Diabetes & Endocrinology Clinical Trials

• Endocrinology
• Diabetes & Metabolic Syndrome
• Diabetes Mellitus
• Myocardial Infarction
• Diabetes & Endocrinology Clinical Trials

The cardiovascular (CV) safety of linagliptin, a dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes mellitus (T2DM) has been supported by a pooled comprehensive analysis of prospectively adjudicated CV events in Phase 3 studies. Odd Erik Johansen, MD, Boehringer-Ingelheim, Asker, Norway, presented the analysis.

The present analysis expands on a previous assessment that showed the CV safety of linagliptin, and a hint of a benefit [Johansen OE et al. Cardiovasc Diabetol 2012], by including recently completed trials with linagliptin. The possibility of CV benefit was also shown in a head-to-head comparison of linagliptin and glimeperide in a noninferiority trial [Gallwitz B et al. Lancet 2012]. CV benefit with linagliptin is being tested prospectively in the CAROLINA study [NCT01243424] against glimepiride and in the CARMELINA study [NCT01897532] against placebo.

The pooled analysis included 9459 patients from 19 United States or multinational, multicenter, double-blind, parallel-group studies. Of these, 5847 patients were randomized to receive linagliptin and 3612 to a comparator for at least 12 weeks and up to 2 years. A prospectively defined, blinded, and independent adjudication of events was used. The primary composite endpoint was CV death, myocardial infarction (MI), stroke, and hospitalization for unstable angina pectoris.

In the pooled analysis, the patients were aged ∼60 years, ∼45% were women, and ∼60% were white. Most patients had normal or mild estimated glomerular filtration rate and had high (∼73%) prior use of a CV medication (aspirin, lipid-lowering agent, or antihypertensive). About a quarter (24.5% linagliptin, 29.0% placebo) of the patients had a Framingham Risk Score >15%.

The drug exposure and the incidence of primary, secondary, and tertiary outcomes in the pooled analysis are detailed in Table 1. Linagliptin, versus the combined comparators, reduced the primary outcome (HR, 0.78; 95% CI, 0.55 to 1.12) and the secondary outcome of CV death, stroke, or MI (HR, 0.74; 95% CI, 0.49 to 1.13). Significant reductions were achieved with linagliptin versus the combined comparators for nonfatal stroke (HR, 0.34; 95% CI, 0.15 to 0.75; p<0.05), and transischemic attack (HR, 0.09; 95% CI, 0.01 to 0.75; p<0.05).

A placebo cohort analysis included 7746 patients from 18 United States or multinational, double-blind, parallel-group studies, of whom 5071 were randomized to linagliptin and 2675 to placebo. In this placebo cohort, from which one active comparator trial was removed, there were fewer primary and secondary outcome events. Linagliptin did not affect the primary outcome compared with placebo (HR, 1.09; 95% CI, 0.68 to 1.75).

Hospitalization for congestive heart failure was assessed in 8 of the trials, which occurred in 12 of 1834 patients (0.7%) in the linagliptin group and 9 of 1175 patients (0.8%) in the comparator groups. The incidence rate per 1000 years at risk was 9.5% and 8.8%, respectively. Linagliptin did not reduce hospitalization for heart failure (HR, 1.04; 95% CI, 0.43 to 2.47).

Thus, in a representative cohort of patients with T2DM, with a diverse background from low to high CV risk and concomitant treatments from treatment-naïve to insulin, linagliptin was not associated with an increased risk for CV events. Based on the limited number of congestive heart failure cases leading to hospitalization, no increased risk with linagliptin was observed.

• © 2013 MD Conference Express®