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

A Meta-Analysis of Amputation Risk in Empagliflozin Studies (1245.25, 1245.110, 1245.121)

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Placebo; Drug: Empagliflozin

• Study Type: Observational
• Enrollment (Actual): 16746

Contacts and Locations

Study Locations

• Germany
  • Ingelheim am Rhein, Germany, 55218
    • Boehringer Ingelheim

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with type 2 diabetes mellitus and increased cardiovascular risk (1245.25), patients with chronic heart failure with preserved ejection fraction (1245.110), and patients with chronic heart failure with reduced ejection fraction (1245.121), who were either treated with empagliflozin or placebo.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

7

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
EMPA-REG - Placebo; Participants of the EMP-REG OUTCOME study (1245.25) who received placebo.	Drug: Placebo; Placebo
EMPA-REG - Empagliflozin low dose; Participants of the EMPA-REG OUTCOME study (1245.25) who received a low dose of empagliflozin once daily (QD).	Drug: Empagliflozin; Empagliflozin once daily
EMPA-REG - Empagliflozin high dose; Participants of the EMP-REG OUTCOME study (1245.25) who received a high dose of empagliflozin once daily (QD).	Drug: Empagliflozin; Empagliflozin once daily
EMPEROR-Preserved - Empagliflozin; Participants of the EMPEROR-Preserved study (1245.110) who received empagliflozin once daily (QD).	Drug: Empagliflozin; Empagliflozin once daily
EMPEROR-Preserved - Placebo; Participants of the EMPEROR-Preserved study (1245.110) who received placebo once daily (QD).	Drug: Placebo; Placebo
EMPEROR-Reduced - Empagliflozin; Participants of the EMPEROR-Reduced study (1245.121) who received empagliflozin once daily (QD).	Drug: Empagliflozin; Empagliflozin once daily
EMPEROR-Reduced - Placebo; Participants of the EMPEROR-Reduced study (1245.121) who received placebo once daily (QD).	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence Rate of Lower Limb Amputation (LLA)	Incidence rate of lower limb amputation (LLA). Incidence rate were provided as rate per 100 patients-years (pt-yrs) calculated as the observed number of patients with event divided by observed time-at-risk over all patients. Time at risk was derived as followed: Patient with event: time at risk in days = date of start of first event - treatment start date + 1. Patients without event: time at risk in days = last date on treatment + 7 days - treatment start date + 1. Abbreviation: pt-yrs = patient-years.	From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence Rate of Adverse Events Related to Amputation	Incidence rate of adverse events (AEs) related to amputation. Incidence rate were provided as rate per 100 patients-years (pt-yrs) calculated as the observed number of patients with event divided by observed time-at-risk over all patients. Time at risk was derived as followed: Patient with event: time at risk in days = date of start of first event - treatment start date + 1. Patients without event: time at risk in days = last date on treatment + 7 days - treatment start date + 1. A search with a pre-defined list of MedDRA preferred terms was performed to identify all AEs related to amputation. These AE included vascular disorders, diabetic-foot-related events, wound/infections, nervous system disorders and volume depletion events. Abbreviation: pt-yrs = patient-years.	From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2021
• Primary Completion (Actual): July 13, 2021
• Study Completion (Actual): July 13, 2021

Study Registration Dates

• First Submitted: June 21, 2021
• First Submitted That Met QC Criteria: June 21, 2021
• First Posted (Actual): June 24, 2021

Study Record Updates

• Last Update Posted (Actual): February 8, 2024
• Last Update Submitted That Met QC Criteria: June 15, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: 1245-0171

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents. Exceptions might apply, e.g. studies in products where Boehringer Ingelheim is not the license holder; studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials; studies conducted in a single center or targeting rare diseases (in case of low number of patients and therefore limitations with anonymization).

For more details refer to: https://www.mystudywindow.com/msw/datatransparency

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No