Study type

Study topic

Human medicinal product
Disease /health condition

Study type

Non-interventional study

Scope of the study

Assessment of risk minimisation measure implementation or effectiveness

Data collection methods

Secondary use of data
Non-interventional study

Non-interventional study design

Systematic review and meta-analysis
Study drug and medical condition

Study drug International non-proprietary name (INN) or common name

EMPAGLIFLOZIN

Medical condition to be studied

Leg amputation

Additional medical condition(s)

Adverse events related to lower limb amputation
Population studied

Short description of the study population

Study 1245.25 included patients with type 2 diabetes mellitus and increased cardiovascular risk. Detailed eligibility criteria can be found in CTR 1245.25 and the key criteria are summarised below.
The key inclusion criteria were:
 Age ≥18 years, diagnosis of T2DM
 Drug-naïve or pretreated with any background therapy
 HbA1c criteria
o Patients who were drug-naïve: HbA1c of 7 to 10%
o Patients with background therapy: HbA1c of 7 to 9%
 BMI ≤45 kg/m2
 With high cardiovascular risk, defined as ≥1 of the following criteria
o History of myocardial infarction (>2 months prior to enrollment)
o Multi-vessel coronary artery disease: ≥2 major vessels or left main coronary artery
o Single-vessel coronary artery disease with no scheduled revascularization/previously unsuccessful revascularization
o Hospital discharge due to unstable angina pectoris (>2 months prior to enrollment)
o History of stroke (>2 months prior to enrollment)
o Peripheral occlusive arterial disease
The key exclusion criteria were:
 Uncontrolled hyperglycemia: fasting plasma glucose >240 mg/dl
 Severe renal impairment defined as eGFR <30 ml/min by MDRD formula
 Intake of an investigational drug in another trial within 30 days prior to intake of study medication in this trial, or participating in another trial (involving an investigational drug and/or follow-up)

Studies 1245.110 and 1245.121
Study 1245.110 will include patients with chronic heart failure with preserved ejection fraction. Study 1245.121 will include patients with chronic heart failure with reduced ejection fraction. Detailed eligibility criteria can be found in CTPs and the key criteria are summarised below.
The key inclusion criteria are:
 Age ≥18 years (Japan, age ≥20 years)
 Chronic HF NYHA class II to IV
 Ejection fraction (EF) and NT-proBNP criteria
o 1245.110: preserved EF (LVEF >40%) and elevated NT-proBNP (>300 pg/ml; >900 pg/ml for patients with atrial fibrillation)
o 1245.121: reduced EF (LVEF ≤40%) and elevated NT-proBNP (≥2500 pg/ml if EF 36 to 40%, ≥1000 pg/ml if EF 31 to 35%, ≥600 pg/ml if EF ≤30% or if EF ≤40% with documented hospitalisation for HF within 12 months prior to screening; for patients with atrial fibrillation, double the level of NT-proBNP is applied for each EF category)
 1245.110 only: structural heart disease within 6 months or documented hospitalisation for HF within 12 months prior to screening
 1245.121 only: stable dose of medical therapy for HF consistent with local and international cardiology guidelines
The key exclusion criteria are:
 Myocardial infarction, coronary artery bypass graft surgery or other major cardiovascular surgery, stroke or transient ischaemic attack ≤90 days before screening
 Heart transplant recipient, or listed for heart transplant
 Acute decompensated HF
 SBP ≥180 mmHg at randomisation
 Symptomatic hypotension and/or SBP <100 mmHg at screening or randomisation
 Impaired renal function defined as eGFR (CKD-EPI)cr <20 ml/min/1.73 m2 or requiring dialysis at screening

Age groups

  • Adult and elderly population (≥18 years)
    • Adults (18 to < 65 years)
      • Adults (18 to < 46 years)
      • Adults (46 to < 65 years)
    • Elderly (≥ 65 years)
      • Adults (65 to < 75 years)
      • Adults (75 to < 85 years)
      • Adults (85 years and over)

Special population of interest

Other

Special population of interest, other

Type 2 diabetes mellitus patients, Chronic heart failure patients

Estimated number of subjects

14000
Study design details

Main study objective

Assess the risk of lower limb amputations in patients treated with empagliflozion

Outcomes

Lower limb amputation, Adverse events related to lower limb amputation

Data analysis plan

This meta-analysis will be exploratory. For the primary outcome of lower limb amputation (LLA) events and for the secondary outcomeof AEs related to amputation, a Cox proportional hazards regression model for modelling the time to first event will be used, includingthe factors study, diabetes mellitus status (T1DM, T2DM, no diabetes), and treatment (all empagliflozin vs. placebo). Study is assumedas fixed effect in this meta-analysis. For treatment comparison, hazard ratios with corresponding 95% CIs as well as corresponding p-values will be presented.