Dataset Information

Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme.

ABSTRACT:

Background

This study investigated the cardiovascular (CV) safety profile of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin versus comparator treatments.

Methods

This 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.

Results

Of 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]).

Conclusions

These results from a large Phase 3 programme support the hypothesis that linagliptin may have CV benefits in patients with T2DM.

SUBMITTER: Johansen OE

PROVIDER: S-EPMC3286367 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Publications

Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme.

Johansen Odd Erik OE Neubacher Dietmar D von Eynatten Maximilian M Patel Sanjay S Woerle Hans-Juergen HJ

Cardiovascular diabetology 20120110

<h4>Background</h4>This study investigated the cardiovascular (CV) safety profile of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin versus comparator treatments.<h4>Methods</h4>This 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, stro ...[more]

PMID: 22234149

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Project description:Background The optimal duration of dual antiplatelet therapy after coronary drug-eluting stent placement in adults with stable coronary artery disease (SCAD) versus acute coronary syndromes (ACS) remains uncertain. Methods and Results This was a prespecified subgroup analysis of the GLOBAL LEADERS trial. Participants were randomly assigned 1:1 to the experimental or reference strategy, stratified by ACS (experimental, n=3750; reference, n=3737) versus SCAD (experimental, n=4230; reference, n=4251). The experimental strategy was 75 to 100 mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month, followed by 23 months of ticagrelor monotherapy. The reference strategy was 75 to 100 mg aspirin daily plus either 75 mg clopidogrel daily (for SCAD) or 90 mg ticagrelor twice daily (for ACS) for 12 months, followed by aspirin monotherapy for 12 months. The primary end point at 2 years was a composite of all-cause mortality or non-fatal centrally adjudicated new Q-wave myocardial infarction. The key secondary safety end point was site-reported Bleeding Academic Research Consortium grade 3 or 5 bleeding. The primary end point occurred in 147 (3.92%) versus 169 (4.52%) patients with ACS (rate ratio [RR], 0.86; 95% CI, 0.69-1.08; P=0.189), and in 157 (3.71%) versus 180 (4.23%) patients with SCAD (RR, 0.87; 95% CI, 0.71-1.08; P=0.221) with experimental and reference strategy, respectively (P-interaction=0.926). Bleeding Academic Research Consortium grade 3 or 5 bleeding occurred in 73 (1.95%) versus 100 (2.68%) patients with ACS (RR, 0.73; 95% CI, 0.54-0.98; P=0.037), and in 90 (2.13%) versus 69 (1.62%) patients with SCAD (RR, 1.32; 95% CI, 0.97-1.81; P=0.081; P-interaction=0.007). Conclusions While there was no evidence for differences in efficacy between treatment strategies by subgroup, the experimental strategy appeared to reduce bleeding risk in patients with ACS but not in patients with SCAD. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01813435.

Project description:In patients with type 2 diabetes mellitus (T2DM), hypertension and microalbuminuria are predictive markers for increased renal and cardiovascular risk. This post hoc analysis of data from a global development program aimed to evaluate the efficacy and safety of linagliptin in a population with joint prevalence of these two vascular risk factors.Data for patients with baseline microalbuminuria (urine albumin-to-creatinine ratio 30-300?mg/g) and hypertension (systolic blood pressure???140?mm Hg and/or diastolic blood pressure???90?mm Hg and/or a history of hypertension; and/or an antihypertensive treatment at baseline) who participated in any of six randomized, placebo-controlled, phase III trials were analyzed. Participants received linagliptin 5?mg daily (alone or in combination with other oral antidiabetic drugs) or placebo for 18 to 24?weeks.Of 3,119 patients, 512 had both microalbuminuria and hypertension (linagliptin, 366; placebo, 146). Baseline mean (SD) HbA1c was 8.3 (0.9)% and 8.4 (0.9)%; median (range) urine albumin-to-creatinine ratio was 60 (30-292) mg/g and 64 (30-298) mg/g; mean (SD) systolic blood pressure was 138 (15) mm Hg and 135 (16) mm Hg; and mean (SD) diastolic blood pressure was 81 (10) mm Hg and 81 (10) mm Hg, for linagliptin and placebo, respectively. Placebo-corrected mean change in HbA1c from baseline to week 18 and week 24 was -0.57% (95% CI: -0.75, -0.39; P?<?0.0001) and -0.59% (95% CI: -0.80, -0.39; P?<?0.0001), respectively. Placebo-corrected mean change in FPG from baseline to week 24 was -21.3?mg/dl (95% CI: -31.0, -11.6; P?<?0.0001). The incidence of drug-related adverse events was similar for linagliptin and placebo (10.4% and 8.2%, respectively). Changes in systolic and diastolic blood pressure, cholesterol and triglyceride levels were similar between linagliptin and placebo.In T2DM patients with the two common vascular risk factors of hypertension and microalbuminuria, linagliptin achieved significant improvements in glycemic control. In this vulnerable patient population at high risk for micro- and macrovascular complications, linagliptin was well tolerated.

Dataset Information

Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme.

Background

Methods

Results

Conclusions

Publications

Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme.

Similar Datasets

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