This Study Combines Data From 3 Other Studies Testing Empagliflozin in Patients With Diabetes or With Chronic Heart Failure. The Study Looks at the Numbers of Patients Who Had Lower Limb Amputations

Boehringer Ingelheim

Status: Completed

Conditions: Diabetes Mellitus, Type 2

Treatments: Drug: Placebo; Drug: Empagliflozin

Study type: Observational

Funder types: Industry

Identifiers

NCT04937816

1245-0171

Details and patient eligibility

About

The primary objective of this exploratory meta-analysis is to evaluate the frequencies, incidence rates, and hazard ratios of lower-limb amputation (LLA) events (primary outcome) and of adverse events related to amputation (secondary outcome) in patients treated with empagliflozin compared with placebo in the pooled population of the long-term studies 1245.25, 1245.110, and 1245.121 (SAF-M1), in the pooled population of studies 1245.110 and 1245.121 (SAFM2), and in each of the 3 studies separately.

Enrollment: 16,746 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria for 1245.25:

• Age ≥18 years, diagnosis of type 2 diabetes mellitus (T2DM)

• Drug-naïve or pretreated with any background therapy

• Glycated haemoglobin (HbA1c) criteria

  • Patients who were drug-naïve: HbA1c of 7 to 10%
  • Patients with background therapy: HbA1c of 7 to 9%

• Body mass index (BMI) ≤45 kg/m2

• With high cardiovascular risk, defined as ≥1 of the following criteria

  • History of myocardial infarction (>2 months prior to enrollment)
  • Multi-vessel coronary artery disease: ≥2 major vessels or left main coronary artery
  • Single-vessel coronary artery disease with no scheduled revascularization/previously unsuccessful revascularization
  • Hospital discharge due to unstable angina pectoris (>2 months prior to enrollment)
  • History of stroke (>2 months prior to enrollment)
  • Peripheral occlusive arterial disease

Inclusion criteria for 1245.110 and 1245.121

• Age ≥18 years (Japan, age ≥20 years)

• Chronic heart failure (HF) new york hear association (NYHA) class II to IV

• Ejection fraction (EF) and N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) criteria

  • 1245.110: preserved EF (Left ventricular ejection fraction (LVEF) >40%) and elevated NT-proBNP (>300 pg/ml; >900 pg/ml for patients with atrial fibrillation)
  • 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

Exclusion criteria for 1245.25

• Uncontrolled hyperglycemia: fasting plasma glucose >240 mg/dl
• Severe renal impairment defined as eGFR <30 ml/min by Modification of diet in renal disease (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)

Exclusion criteria for 1245.110 and 1245.121

• 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
• Systolic blood pressure (SBP) ≥180 mmHg at randomisation
• Symptomatic hypotension and/or SBP <100 mmHg at screening or randomisation
• Impaired renal function defined as Estimated glomerular filtration rate (eGFR) Chronic Kidney Disease Epidemiology Collaboration Equation (based on serum creatinine value) <20 ml/min/1.73 m2 or requiring dialysis at screening

Trial design

16,746 participants in 7 patient groups

EMPA-REG - Placebo

Description:

Participants of the EMP-REG OUTCOME study (1245.25) who received placebo.

Treatment:

Drug: Placebo

EMPA-REG - Empagliflozin low dose

Description:

Participants of the EMPA-REG OUTCOME study (1245.25) who received a low dose of empagliflozin once daily (QD).

Treatment:

Drug: Empagliflozin

EMPA-REG - Empagliflozin high dose

Description:

Participants of the EMP-REG OUTCOME study (1245.25) who received a high dose of empagliflozin once daily (QD).

Treatment:

Drug: Empagliflozin

EMPEROR-Preserved - Empagliflozin

Description:

Participants of the EMPEROR-Preserved study (1245.110) who received empagliflozin once daily (QD).

Treatment:

Drug: Empagliflozin

EMPEROR-Preserved - Placebo

Description:

Participants of the EMPEROR-Preserved study (1245.110) who received placebo once daily (QD).

Treatment:

Drug: Placebo

EMPEROR-Reduced - Empagliflozin

Description:

Participants of the EMPEROR-Reduced study (1245.121) who received empagliflozin once daily (QD).

Treatment:

Drug: Empagliflozin

EMPEROR-Reduced - Placebo

Description:

Participants of the EMPEROR-Reduced study (1245.121) who received placebo once daily (QD).

Treatment:

Drug: Placebo