Abstract
BackgroundThis study investigated the cardiovascular (CV) safety profile of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin versus comparator treatments.MethodsThis was a pre-specified meta-analysis of CV events in linagliptin or comparator-treated patients with type 2 diabetes mellitus (T2DM) from eight Phase 3 studies. All suspected CV events were prospectively adjudicated by a blinded independent expert committee. The primary endpoint was a composite of CV death, stroke, myocardial infarction, and hospitalization for unstable angina. Three secondary composite endpoints derived from the adjudicated CV events were also pre-specified. Risk estimates were calculated using several statistical methods including Cox regression analysis.ResultsOf 5239 treated patients (mean ± SD HbA1c 65 ± 10 mmol/mol [8.0 ± 0.9%], age 58 ± 10 years, BMI 29 ± 5 kg/m2), 3319 received linagliptin once daily (5 mg, 3159; 10 mg, 160) and 1920 received comparators (placebo, 977; glimepiride 1-4 mg, 781; voglibose 0.6 mg, 162). Cumulative exposure (patient-years) was 2060 for linagliptin and 1372 for comparators. Primary CV events occurred in 11 (0.3%) patients receiving linagliptin and 23 (1.2%) receiving comparators. The hazard ratio (HR) for the primary endpoint showed significantly lower risk with linagliptin than comparators (HR 0.34 [95% confidence interval (CI) 0.16-0.70]) as did estimates for all secondary endpoints (HR ranging from 0.34 to 0.55 [all upper 95% CIs < 1.0]).ConclusionsThese results from a large Phase 3 programme support the hypothesis that linagliptin may have CV benefits in patients with T2DM.
Highlights
This study investigated the cardiovascular (CV) safety profile of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin versus comparator treatments
Changes were of similar magnitude in both groups for all parameters except for HbA1c, where a meaningful HbA1c reduction was seen for linagliptin, and body weight, where a modest weight increase was seen in the total comparator group
These findings were expected since linagliptin is a glucose-lowering drug and were provided to all patients in the linagliptin group, whereas ~50% of patients in the comparator cohort received placebo
Summary
This study investigated the cardiovascular (CV) safety profile of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin versus comparator treatments. Recent large outcomes trials of glycaemic intervention in CV events possibly due to unanticipated pleiotropic CV effects [9]. In light of these concerns, regulatory authorities, including the US Food and Drug Administration (FDA) and the European Medicines Agency, have issued guidance that the development programmes for all new glucose-lowering therapies must show that treatment confers no unacceptable increases in CV risk [10,11]. Dipeptidyl peptidase (DPP)-4 inhibitors, which enhance postprandial levels of the incretin hormones glucagonlike peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), have limited side effects [12]. The glucoregulatory actions of incretins include glucosedependent promotion of insulin secretion, glucagon suppression, delayed gastric emptying, and increased satiety
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