Diabetes Mellitus, Type 2
Conditions
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.
Interventions
DRUGPlacebo
Placebo
DRUGEmpagliflozin
Empagliflozin once daily
Sponsors
Boehringer Ingelheim
Study design
Observational model
OTHER
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rate of Lower Limb Amputation (LLA) | From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rate of Adverse Events Related to Amputation | From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days. | 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. |
Countries
Germany
Participant flow
Recruitment details
This meta-analysis includes three randomised, placebo-controlled, double-blind, parallel-group and event-driven studies (NCT01131676, NCT03057951, NCT03057977) to evaluate the risk of lower-limb amputation (LLA) in patients treated with empagliflozin compared to placebo in the pooled population (SAF-M1 vs. SAF-M2).
Pre-assignment details
As this is a meta-analysis of three independent trials, all subjects were screened for eligibility prior to participation of the respective trial.
Participants by arm
| Arm | Count |
|---|---|
| Trial NCT01131676: Placebo Oral administration of Placebo matching empagliflozin 10 or 25 milligram (mg) (1 tablet once daily) in patients with type 2 diabetes mellitus (T2DM). | 2,333 |
| Trial NCT01131676: Empagliflozin 10 mg 1 film-coated tablet of 10 mg empagliflozin (BI 10773) was administered orally once daily in patients with T2DM. | 2,345 |
| Trial NCT01131676: Empagliflozin 25 mg 1 film-coated tablet of 25 mg empagliflozin (BI 10773) was administered orally once daily in patients with T2DM. | 2,342 |
| Trial NCT03057951: Placebo 1 film-coated tablet of matching placebo was administered orally once daily in patients with chronic heart failure with preserved ejection fraction (HFpEF). | 2,989 |
| Trial NCT03057951: Empagliflozin 10 mg 1 film-coated tablet of 10 milligram (mg) of empagliflozin (BI 10773) was administered orally once daily in patients with chronic heart failure with preserved ejection fraction (HFpEF). | 2,996 |
| Trial NCT03057977: Placebo 1 film-coated tablet of matching placebo was administered orally once daily in patients with heart failure with reduced ejection fraction (HFrEF). | 1,863 |
| Trial NCT03057977: Empagliflozin 10 mg 1 film-coated tablet of 10 milligram (mg) empagliflozin (BI 10773) was administered orally once daily in patients with heart failure with reduced ejection fraction (HFrEF). | 1,863 |
| Total | 16,731 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 303 | 267 | 273 | 553 | 575 | 343 | 337 |
| Overall Study | Lost to Follow-up | 15 | 9 | 6 | 6 | 16 | 11 | 17 |
| Overall Study | Not treated | 4 | 2 | 2 | 2 | 1 | 4 | 0 |
| Overall Study | Other than stated below | 173 | 143 | 125 | 44 | 45 | 28 | 31 |
| Overall Study | Patient refusal to continue, not due to AE | 172 | 118 | 122 | 304 | 284 | 124 | 92 |
| Overall Study | Protocol Violation | 15 | 15 | 12 | 30 | 24 | 5 | 5 |
| Overall Study | Study drug stopped, reason missing | 5 | 3 | 4 | 6 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Trial NCT01131676: Placebo | Trial NCT01131676: Empagliflozin 10 mg | Trial NCT01131676: Empagliflozin 25 mg | Trial NCT03057951: Placebo | Trial NCT03057951: Empagliflozin 10 mg | Trial NCT03057977: Placebo | Trial NCT03057977: Empagliflozin 10 mg | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 63.2 Years STANDARD_DEVIATION 8.8 | 63.0 Years STANDARD_DEVIATION 8.6 | 63.2 Years STANDARD_DEVIATION 8.6 | 71.9 Years STANDARD_DEVIATION 9.6 | 71.8 Years STANDARD_DEVIATION 9.3 | 66.5 Years STANDARD_DEVIATION 11.2 | 67.2 Years STANDARD_DEVIATION 10.8 | 67.1 Years STANDARD_DEVIATION 10.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 418 Participants | 432 Participants | 415 Participants | 753 Participants | 770 Participants | 613 Participants | 616 Participants | 4017 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1912 Participants | 1909 Participants | 1926 Participants | 2235 Participants | 2226 Participants | 1175 Participants | 1164 Participants | 12547 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 1 Participants | 1 Participants | 0 Participants | 75 Participants | 83 Participants | 167 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 20 Participants | 11 Participants | 23 Participants | 104 Participants | 90 Participants | 24 Participants | 15 Participants | 287 Participants |
| Race (NIH/OMB) Asian | 511 Participants | 505 Participants | 501 Participants | 411 Participants | 413 Participants | 334 Participants | 337 Participants | 3012 Participants |
| Race (NIH/OMB) Black or African American | 120 Participants | 119 Participants | 118 Participants | 125 Participants | 133 Participants | 134 Participants | 123 Participants | 872 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 75 Participants | 60 Participants | 33 Participants | 28 Participants | 196 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 4 Participants | 3 Participants | 3 Participants | 19 Participants | 14 Participants | 6 Participants | 8 Participants | 57 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 31 Participants | 27 Participants | 61 Participants |
| Race (NIH/OMB) White | 1678 Participants | 1707 Participants | 1696 Participants | 2254 Participants | 2285 Participants | 1301 Participants | 1325 Participants | 12246 Participants |
| Sex: Female, Male Female | 653 Participants | 692 Participants | 659 Participants | 1336 Participants | 1338 Participants | 453 Participants | 437 Participants | 5568 Participants |
| Sex: Female, Male Male | 1680 Participants | 1653 Participants | 1683 Participants | 1653 Participants | 1658 Participants | 1410 Participants | 1426 Participants | 11163 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
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.
Time frame: From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days.
Population: Treated Set: Patients treated with at least 1 dose of study medication. Results are reported by the pooled population (SAF-M1 and SAF-M2) and for each study separately. For trial NCT01131676, 10 mg and 25 mg were combined, as the overall safety profile is similar for empagliflozin 10 mg and 25 mg. This approach was agreed with the European Medicines Agency (EMA).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SAF-M1 Placebo | Incidence Rate of Lower Limb Amputation (LLA) | 0.40 Patients with events per 100pt-yrs |
| SAF-M1 Empagliflozin | Incidence Rate of Lower Limb Amputation (LLA) | 0.48 Patients with events per 100pt-yrs |
| SAF-M2 Placebo | Incidence Rate of Lower Limb Amputation (LLA) | 0.27 Patients with events per 100pt-yrs |
| SAF-M2 Empagliflozin 10 mg | Incidence Rate of Lower Limb Amputation (LLA) | 0.23 Patients with events per 100pt-yrs |
| Trial NCT01131676: Placebo | Incidence Rate of Lower Limb Amputation (LLA) | 0.59 Patients with events per 100pt-yrs |
| Trial NCT01131676: Empagliflozin 10 mg or 25 mg | Incidence Rate of Lower Limb Amputation (LLA) | 0.64 Patients with events per 100pt-yrs |
| Trial NCT03057951: Placebo | Incidence Rate of Lower Limb Amputation (LLA) | 0.27 Patients with events per 100pt-yrs |
| Trial NCT03057951: Empagliflozin 10 mg | Incidence Rate of Lower Limb Amputation (LLA) | 0.20 Patients with events per 100pt-yrs |
| Trial NCT03057977: Placebo | Incidence Rate of Lower Limb Amputation (LLA) | 0.27 Patients with events per 100pt-yrs |
| Trial NCT03057977: Empagliflozin 10 mg | Incidence Rate of Lower Limb Amputation (LLA) | 0.31 Patients with events per 100pt-yrs |
p-value: 0.927695% CI: [0.73, 1.42]Regression, Cox
p-value: 0.620595% CI: [0.45, 1.6]Regression, Cox
Comparison: Empagliflozin (10 mg + 25 mg) versus Placebo.p-value: 0.676895% CI: [0.73, 1.63]Regression, Cox
p-value: 0.429495% CI: [0.34, 1.59]Regression, Cox
p-value: 0.782695% CI: [0.39, 3.47]Regression, Cox
Secondary
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.
Time frame: From first to last dose of study medication plus 7 days to account for the residual drug effect, up to 1639 days.
Population: Treated Set: Patients treated with at least 1 dose of study medication. Results are reported by the pooled population (SAF-M1 and SAF-M2) and for each study separately. For trial NCT01131676, 10 mg and 25 mg were combined, as the overall safety profile is similar for empagliflozin 10 mg and 25 mg. This approach was agreed with the European Medicines Agency (EMA).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SAF-M1 Placebo | Incidence Rate of Adverse Events Related to Amputation | Diabetic foot related AE | 0.50 Patients with events per 100 pt-yrs |
| SAF-M1 Placebo | Incidence Rate of Adverse Events Related to Amputation | Volume depletion | 0.67 Patients with events per 100 pt-yrs |
| SAF-M1 Placebo | Incidence Rate of Adverse Events Related to Amputation | Infections potentially related to LLA | 2.19 Patients with events per 100 pt-yrs |
| SAF-M1 Placebo | Incidence Rate of Adverse Events Related to Amputation | Wound/infection | 0.86 Patients with events per 100 pt-yrs |
| SAF-M1 Placebo | Incidence Rate of Adverse Events Related to Amputation | Nervous system disorder | 1.54 Patients with events per 100 pt-yrs |
| SAF-M1 Placebo | Incidence Rate of Adverse Events Related to Amputation | Vascular adverse event | 1.48 Patients with events per 100 pt-yrs |
| SAF-M1 Empagliflozin | Incidence Rate of Adverse Events Related to Amputation | Infections potentially related to LLA | 2.04 Patients with events per 100 pt-yrs |
| SAF-M1 Empagliflozin | Incidence Rate of Adverse Events Related to Amputation | Vascular adverse event | 1.57 Patients with events per 100 pt-yrs |
| SAF-M1 Empagliflozin | Incidence Rate of Adverse Events Related to Amputation | Volume depletion | 0.65 Patients with events per 100 pt-yrs |
| SAF-M1 Empagliflozin | Incidence Rate of Adverse Events Related to Amputation | Nervous system disorder | 1.81 Patients with events per 100 pt-yrs |
| SAF-M1 Empagliflozin | Incidence Rate of Adverse Events Related to Amputation | Diabetic foot related AE | 0.64 Patients with events per 100 pt-yrs |
| SAF-M1 Empagliflozin | Incidence Rate of Adverse Events Related to Amputation | Wound/infection | 0.86 Patients with events per 100 pt-yrs |
| SAF-M2 Placebo | Incidence Rate of Adverse Events Related to Amputation | Vascular adverse event | 1.27 Patients with events per 100 pt-yrs |
| SAF-M2 Placebo | Incidence Rate of Adverse Events Related to Amputation | Diabetic foot related AE | 0.32 Patients with events per 100 pt-yrs |
| SAF-M2 Placebo | Incidence Rate of Adverse Events Related to Amputation | Wound/infection | 0.65 Patients with events per 100 pt-yrs |
| SAF-M2 Placebo | Incidence Rate of Adverse Events Related to Amputation | Volume depletion | 0.95 Patients with events per 100 pt-yrs |
| SAF-M2 Placebo | Incidence Rate of Adverse Events Related to Amputation | Infections potentially related to LLA | 1.85 Patients with events per 100 pt-yrs |
| SAF-M2 Placebo | Incidence Rate of Adverse Events Related to Amputation | Nervous system disorder | 0.85 Patients with events per 100 pt-yrs |
| SAF-M2 Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Nervous system disorder | 0.92 Patients with events per 100 pt-yrs |
| SAF-M2 Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Infections potentially related to LLA | 1.78 Patients with events per 100 pt-yrs |
| SAF-M2 Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Diabetic foot related AE | 0.46 Patients with events per 100 pt-yrs |
| SAF-M2 Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Vascular adverse event | 1.21 Patients with events per 100 pt-yrs |
| SAF-M2 Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Wound/infection | 0.46 Patients with events per 100 pt-yrs |
| SAF-M2 Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Volume depletion | 1.16 Patients with events per 100 pt-yrs |
| Trial NCT01131676: Placebo | Incidence Rate of Adverse Events Related to Amputation | Nervous system disorder | 2.53 Patients with events per 100 pt-yrs |
| Trial NCT01131676: Placebo | Incidence Rate of Adverse Events Related to Amputation | Vascular adverse event | 1.77 Patients with events per 100 pt-yrs |
| Trial NCT01131676: Placebo | Incidence Rate of Adverse Events Related to Amputation | Diabetic foot related AE | 0.75 Patients with events per 100 pt-yrs |
| Trial NCT01131676: Placebo | Incidence Rate of Adverse Events Related to Amputation | Infections potentially related to LLA | 2.64 Patients with events per 100 pt-yrs |
| Trial NCT01131676: Placebo | Incidence Rate of Adverse Events Related to Amputation | Wound/infection | 1.14 Patients with events per 100 pt-yrs |
| Trial NCT01131676: Placebo | Incidence Rate of Adverse Events Related to Amputation | Volume depletion | 0.28 Patients with events per 100 pt-yrs |
| Trial NCT01131676: Empagliflozin 10 mg or 25 mg | Incidence Rate of Adverse Events Related to Amputation | Infections potentially related to LLA | 2.22 Patients with events per 100 pt-yrs |
| Trial NCT01131676: Empagliflozin 10 mg or 25 mg | Incidence Rate of Adverse Events Related to Amputation | Wound/infection | 1.12 Patients with events per 100 pt-yrs |
| Trial NCT01131676: Empagliflozin 10 mg or 25 mg | Incidence Rate of Adverse Events Related to Amputation | Vascular adverse event | 1.81 Patients with events per 100 pt-yrs |
| Trial NCT01131676: Empagliflozin 10 mg or 25 mg | Incidence Rate of Adverse Events Related to Amputation | Volume depletion | 0.32 Patients with events per 100 pt-yrs |
| Trial NCT01131676: Empagliflozin 10 mg or 25 mg | Incidence Rate of Adverse Events Related to Amputation | Nervous system disorder | 2.41 Patients with events per 100 pt-yrs |
| Trial NCT01131676: Empagliflozin 10 mg or 25 mg | Incidence Rate of Adverse Events Related to Amputation | Diabetic foot related AE | 0.76 Patients with events per 100 pt-yrs |
| Trial NCT03057951: Placebo | Incidence Rate of Adverse Events Related to Amputation | Vascular adverse event | 1.21 Patients with events per 100 pt-yrs |
| Trial NCT03057951: Placebo | Incidence Rate of Adverse Events Related to Amputation | Volume depletion | 0.90 Patients with events per 100 pt-yrs |
| Trial NCT03057951: Placebo | Incidence Rate of Adverse Events Related to Amputation | Nervous system disorder | 0.92 Patients with events per 100 pt-yrs |
| Trial NCT03057951: Placebo | Incidence Rate of Adverse Events Related to Amputation | Wound/infection | 0.61 Patients with events per 100 pt-yrs |
| Trial NCT03057951: Placebo | Incidence Rate of Adverse Events Related to Amputation | Infections potentially related to LLA | 1.97 Patients with events per 100 pt-yrs |
| Trial NCT03057951: Placebo | Incidence Rate of Adverse Events Related to Amputation | Diabetic foot related AE | 0.38 Patients with events per 100 pt-yrs |
| Trial NCT03057951: Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Nervous system disorder | 0.99 Patients with events per 100 pt-yrs |
| Trial NCT03057951: Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Vascular adverse event | 1.17 Patients with events per 100 pt-yrs |
| Trial NCT03057951: Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Wound/infection | 0.48 Patients with events per 100 pt-yrs |
| Trial NCT03057951: Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Volume depletion | 1.16 Patients with events per 100 pt-yrs |
| Trial NCT03057951: Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Infections potentially related to LLA | 1.75 Patients with events per 100 pt-yrs |
| Trial NCT03057951: Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Diabetic foot related AE | 0.30 Patients with events per 100 pt-yrs |
| Trial NCT03057977: Placebo | Incidence Rate of Adverse Events Related to Amputation | Vascular adverse event | 1.44 Patients with events per 100 pt-yrs |
| Trial NCT03057977: Placebo | Incidence Rate of Adverse Events Related to Amputation | Diabetic foot related AE | 0.18 Patients with events per 100 pt-yrs |
| Trial NCT03057977: Placebo | Incidence Rate of Adverse Events Related to Amputation | Volume depletion | 1.08 Patients with events per 100 pt-yrs |
| Trial NCT03057977: Placebo | Incidence Rate of Adverse Events Related to Amputation | Wound/infection | 0.76 Patients with events per 100 pt-yrs |
| Trial NCT03057977: Placebo | Incidence Rate of Adverse Events Related to Amputation | Infections potentially related to LLA | 1.57 Patients with events per 100 pt-yrs |
| Trial NCT03057977: Placebo | Incidence Rate of Adverse Events Related to Amputation | Nervous system disorder | 0.67 Patients with events per 100 pt-yrs |
| Trial NCT03057977: Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Volume depletion | 1.16 Patients with events per 100 pt-yrs |
| Trial NCT03057977: Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Nervous system disorder | 0.75 Patients with events per 100 pt-yrs |
| Trial NCT03057977: Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Vascular adverse event | 1.33 Patients with events per 100 pt-yrs |
| Trial NCT03057977: Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Wound/infection | 0.40 Patients with events per 100 pt-yrs |
| Trial NCT03057977: Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Diabetic foot related AE | 0.84 Patients with events per 100 pt-yrs |
| Trial NCT03057977: Empagliflozin 10 mg | Incidence Rate of Adverse Events Related to Amputation | Infections potentially related to LLA | 1.88 Patients with events per 100 pt-yrs |
Comparison: Time to first vascular AE (SAF-M1)p-value: 0.994695% CI: [0.83, 1.2]Regression, Cox
Comparison: Time to first vascular AE (SAF-M2)p-value: 0.747495% CI: [0.72, 1.27]Regression, Cox
Comparison: Time to first vascular AE (Trial NCT01131676, all empagliflozin (10 and 25 mg vs. Placebo))p-value: 0.794395% CI: [0.81, 1.31]Regression, Cox
Comparison: Time to first vascular AE (Trial NCT03057951)p-value: 0.851895% CI: [0.69, 1.36]Regression, Cox
Comparison: Time to first vascular AE (Trial NCT03057977)p-value: 0.76695% CI: [0.56, 1.53]Regression, Cox
Comparison: Time to first diabetic foot related AE (SAF-M1)p-value: 0.361295% CI: [0.85, 1.55]Regression, Cox
Comparison: Time to first diabetic foot related AE (SAF-M2)p-value: 0.16195% CI: [0.86, 2.4]Regression, Cox
Comparison: Time to first diabetic foot related AE (Trial NCT01131676, all empagliflozin (10 and 25 mg) vs. Placebo)p-value: 0.912895% CI: [0.71, 1.47]Regression, Cox
Comparison: Time to first diabetic foot related AE (Trial NCT03057951)p-value: 0.527695% CI: [0.43, 1.54]Regression, Cox
Comparison: Time to first diabetic foot related AE (Trial NCT03057977)p-value: 0.004895% CI: [1.6, 13.87]Regression, Cox
Comparison: Time to first infections potentially related to LLA's (SAF-M1)p-value: 0.152695% CI: [0.77, 1.04]Regression, Cox
Comparison: Time to first infection potentially related to LLA's (SAF-M2)p-value: 0.74395% CI: [0.76, 1.21]Regression, Cox
Comparison: Time to first infections potentially related to LLA (Trial NCT01131676, all Empagliflozin (10 mg and 25 mg) vs. Placebo)p-value: 0.104995% CI: [0.69, 1.04]Regression, Cox
Comparison: Time to first infections potentially related to LLA (Trial NCT03057951)p-value: 0.39595% CI: [0.67, 1.17]Regression, Cox
Comparison: Time to first infections potentially related to LLA (Trial NCT03057977)p-value: 0.442995% CI: [0.76, 1.87]Regression, Cox
Comparison: Time to first wound/infection (SAF-M1)p-value: 0.339695% CI: [0.7, 1.13]Regression, Cox
Comparison: Time to first wound/infection (SAF-M2)p-value: 0.10595% CI: [0.46, 1.08]Regression, Cox
Comparison: Time to first wound/infection (Trial NCT01131676, all Empagliflozin (10 mg and 25 mg) vs Placebo)p-value: 0.991995% CI: [0.74, 1.35]Regression, Cox
Comparison: Time to first wound/infection (Trial NCT03057951)p-value: 0.363495% CI: [0.48, 1.31]Regression, Cox
Comparison: Time to first wound/infection (Trial NCT03057977)p-value: 0.117795% CI: [0.23, 1.18]Regression, Cox
Comparison: Time to first nervous system disorder (SAF-M1)p-value: 0.999295% CI: [0.84, 1.19]Regression, Cox
Comparison: Time to first nervous system disorder (SAF-M2)p-value: 0.627495% CI: [0.78, 1.52]Regression, Cox
Comparison: Time to first nervous system disorder (Trial NCT01131676, all Empagliflozin (10 mg and 25 mg) vs Placebo)p-value: 0.759795% CI: [0.79, 1.19]Regression, Cox
Comparison: Time to first nervous system disorder (Trial NCT03057951)p-value: 0.706795% CI: [0.74, 1.57]Regression, Cox
Comparison: time to first nervous system disorder (Trial NCT03057977)p-value: 0.740495% CI: [0.56, 2.25]Regression, Cox
Comparison: Time to first volume depletion AE (SAF-M1)p-value: 0.176595% CI: [0.92, 1.58]Regression, Cox
Comparison: Time to first volume depletion AE (SAF-M2)p-value: 0.197895% CI: [0.9, 1.66]Regression, Cox
Comparison: Time to first volume depletion (Trial NCT01131676, all Empagliflozin (10 mg and 25 mg) vs Placebo)p-value: 0.656195% CI: [0.64, 2.05]Regression, Cox
Comparison: Time to first volume depletion (Trial NCT03057951)p-value: 0.169995% CI: [0.9, 1.87]Regression, Cox
Comparison: Time to first volume depletion (Trial NCT03057977)p-value: 0.794495% CI: [0.62, 1.87]Regression, Cox