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

Cardiovasc Diabetol. 2012 Jan 10;11:3. doi: 10.1186/1475-2840-11-3.

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.

Trial registration: ClinicalTrials.gov NCT00602472 NCT00621140 NCT00622284 NCT00641043 NCT00654381 NCT00740051 NCT00819091.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Angina, Unstable / etiology
  • Angina, Unstable / prevention & control
  • Biomarkers / blood
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / mortality
  • Cardiovascular Diseases / prevention & control*
  • Clinical Trials, Phase III as Topic
  • Diabetes Complications / etiology
  • Diabetes Complications / mortality
  • Diabetes Complications / prevention & control*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / mortality
  • Dipeptidyl-Peptidase IV Inhibitors / adverse effects
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
  • Evidence-Based Medicine
  • Female
  • Glycated Hemoglobin A / metabolism
  • Hospitalization / statistics & numerical data
  • Humans
  • Linagliptin
  • Male
  • Middle Aged
  • Myocardial Infarction / etiology
  • Myocardial Infarction / prevention & control
  • Patient Safety
  • Proportional Hazards Models
  • Prospective Studies
  • Purines / adverse effects*
  • Quinazolines / adverse effects*
  • Randomized Controlled Trials as Topic
  • Risk Assessment
  • Risk Factors
  • Stroke / etiology
  • Stroke / prevention & control
  • Treatment Outcome

Substances

  • Biomarkers
  • Blood Glucose
  • Dipeptidyl-Peptidase IV Inhibitors
  • Glycated Hemoglobin A
  • Purines
  • Quinazolines
  • hemoglobin A1c protein, human
  • Linagliptin

Associated data

  • ClinicalTrials.gov/NCT00602472
  • ClinicalTrials.gov/NCT00621140
  • ClinicalTrials.gov/NCT00622284
  • ClinicalTrials.gov/NCT00641043
  • ClinicalTrials.gov/NCT00654381
  • ClinicalTrials.gov/NCT00740051
  • ClinicalTrials.gov/NCT00819091