Clinical trial NCT04937816: 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
Official title: A Meta-Analysis of Amputation Risk in Empagliflozin Studies (1245.25, 1245.110, 1245.121)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2021-06-24
Enrollment: 16746
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: RETROSPECTIVE
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.

Brief summary: 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.


Eligibility 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

Primary outcomes:
measure: Incidence Rate of Lower Limb Amputation (LLA)
timeFrame: From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days.
Secondary outcomes:
measure: Incidence Rate of Adverse Events Related to Amputation
timeFrame: From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days.
Other outcomes:
Locations:
city: Ingelheim am Rhein
country: Germany
facility: Boehringer Ingelheim
Study officials:
References: