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

Study Overview
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Brief Summary
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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.

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

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Placebo
* Drug: Empagliflozin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of lower-limb amputation (LLA) events |  | Up to 81 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events related to amputation |  | Up to 81 months. |