Type2 Diabetes, Heart Failure
Conditions
Keywords
type 2 diabetes, heart failure, ertugliflozin, Global longitudinal strain (GLS)
Brief summary
The aim of this study is to investigate the beneficial role of ertugliflozin, a new SGLT2 inhibitor, in cardiac function via measuring GLS as well as other hemodynamic factors using echocardiogram in patients with T2D and HF, who are not controlled with oral antidiabetic medications including DPP4 inhibitors.
Detailed description
This study is a phase 3, randomized, double-blind, active-competitor, parallel-group study that is anticipated to enroll 120 patients. Patients taking metformin and/or DPP4 inhibitors as per local label for ≥12 weeks without a dose adjustment before enrollment will be eligible for screening. All patients will have a screening period comprised of an up to 2-week screening phase prior to randomization. In order to qualify for randomization, patients must demonstrate compliance based upon pill count (80%) and discretion of the investigators during the Run-in phase. Glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) will be masked to patients after randomization. To prevent partial unblinding, urinary glucose excretion (UGE) results will be masked to patients. Urine glucose, albumin, calcium, and creatinine will be measured separately on-site visits.
Interventions
DRUGErtugliflozin
Ertugliflozin as add-on to Metformin and/or DPP4 inhibitors in patients with inadequately controlled type 2 diabetes
DRUGPlacebo
Placebo as add-on to Metformin and/or DPP4 inhibitors in patients with inadequately controlled type 2 diabetes
Sponsors
MSD Korea Ltd.
Soo Lim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients with T2D taking oral antidiabetic medications (metformin and/or DPP4 inhibitors) except SGLT2 inhibitors for at least 12 weeks without a dose adjustment before enrollment. * eGFR ≥ 45 mL/min/1.73 m2. * Stage B HF identified on the basis of either structural or functional markers.
Exclusion criteria
* Type 1 diabetes mellitus * At the time of screening age \<20 years * HbA1c \<7% or HbA1c \>9.5% at Screening * FPG \>15 mmol/L (270 mg/dL) measured by the laboratory at Screening (Visit 1), and confirmed (\>15 mmol/L \[\>270 mg/dL\]) by a repeat test before randomization * Treated with insulin and/or GLP-1R agonist within 12 weeks preceding the Screening Visit. * Women of childbearing potential with no effective contraceptive method * History of gastric surgery including history of gastric banding within 3 years before the Screening Visit * History of diabetic ketoacidosis or nonketotic hyperosmolar coma prior to the Screening Visit * Mean blood pressure after 3 separate measurements \>180 mmHg in systolic blood pressure (SBP) or \>95 mmHg in diastolic blood pressure (DBP) * Patients with current or prior symptoms of HF. * Patients with severe anemia, severe respiratory, hepatic, neurological, psychiatric disorders or active malignant tumor or other major systemic disease or patients with short life expectancy making implementation of the protocol or interpretation of the study results difficult * Aspartate aminotransferase and/or alanine aminotransferase: \>3 times the upper limit of the normal laboratory range (ULN) * Total bilirubin: \>1.5 times ULN (except in case of Gilbert's syndrome) * Use of systemic glucocorticoids (excluding topical or ophthalmic, application or inhaled forms) for more than 10 consecutive days within 90 days prior to the Screening Visit * Patient who has taken other investigational drugs or prohibited therapy for this study within 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Left Ventricular Global Longitudinal Strain (LVGLS) | Baseline, Week 24 | Change in LVGLS after 24 weeks of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Left Ventricular Ejection Fraction (LVEF) | Baseline, Week 24 | Change in LVEF after 24 weeks of treatment |
| Left Ventricular Mass Index (LVMI) | Baseline, Week 24 | Change in LVMI after 24 weeks of treatment |
| E/e' Ratio | Baseline, Week 24 | Change in E/e' ratio after 24 weeks of treatment |
| Left Atrium Ventricular Index (LAVI) | Baseline, Week 24 | Change in LVVI after 24 weeks of treatment |
| Left Ventricular End-diastolic Volume (LVEDV) | Baseline, Week 24 | Change in LVEDV after 24 weeks of treatment |
Other
| Measure | Time frame |
|---|---|
| Angiotensin-converting Enzyme 2 (ACE2) | Baseline, Week 24 |
| Angiotensin (1-7) | Baseline, Week 24 |
| Troponin-T | Baseline, Week 24 |
| N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) | Baseline, Week 24 |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intervention Group Ertugliflozin 5 mg once daily | 51 |
| Control Group Placebo once daily | 51 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Intervention Group | Control Group | Total |
|---|---|---|---|
| Age, Continuous | 62.5 years STANDARD_DEVIATION 9.9 | 65.3 years STANDARD_DEVIATION 8.4 | 63.9 years STANDARD_DEVIATION 9.2 |
| Body mass index | 26.3 kg/m2 STANDARD_DEVIATION 2.9 | 26.4 kg/m2 STANDARD_DEVIATION 3.6 | 26.4 kg/m2 STANDARD_DEVIATION 2.9 |
| Dyslipidemia | 48 participants | 41 participants | 89 participants |
| Estimated glomerular filtration rate | 90.1 mL/min/1.73 m2 STANDARD_DEVIATION 17.6 | 86.9 mL/min/1.73 m2 STANDARD_DEVIATION 16.8 | 88.5 mL/min/1.73 m2 STANDARD_DEVIATION 17.3 |
| Glycated hemoglobin | 8.3 % STANDARD_DEVIATION 1 | 8.4 % STANDARD_DEVIATION 1.1 | 8.4 % STANDARD_DEVIATION 1.1 |
| Hypertension | 35 participants | 35 participants | 70 participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 17 Participants | 22 Participants | 39 Participants |
| Sex: Female, Male Male | 34 Participants | 29 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 51 | 0 / 51 |
| other Total, other adverse events | 6 / 51 | 5 / 51 |
| serious Total, serious adverse events | 0 / 51 | 0 / 51 |
Outcome results
Primary
Left Ventricular Global Longitudinal Strain (LVGLS)
Change in LVGLS after 24 weeks of treatment
Time frame: Baseline, Week 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin Group | Left Ventricular Global Longitudinal Strain (LVGLS) | 16.6 % of LVGLS | Standard Deviation 2.8 |
| Control Group | Left Ventricular Global Longitudinal Strain (LVGLS) | 16.4 % of LVGLS | Standard Deviation 2.6 |
Secondary
E/e' Ratio
Change in E/e' ratio after 24 weeks of treatment
Time frame: Baseline, Week 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin Group | E/e' Ratio | 10.6 ratio | Standard Deviation 3.1 |
| Control Group | E/e' Ratio | 10.4 ratio | Standard Deviation 2.9 |
Secondary
Left Atrium Ventricular Index (LAVI)
Change in LVVI after 24 weeks of treatment
Time frame: Baseline, Week 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin Group | Left Atrium Ventricular Index (LAVI) | 35.5 mL/m2 | Standard Deviation 11.3 |
| Control Group | Left Atrium Ventricular Index (LAVI) | 35.3 mL/m2 | Standard Deviation 11.1 |
Secondary
Left Ventricular Ejection Fraction (LVEF)
Change in LVEF after 24 weeks of treatment
Time frame: Baseline, Week 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin Group | Left Ventricular Ejection Fraction (LVEF) | 61.3 % of LVEF | Standard Deviation 7 |
| Control Group | Left Ventricular Ejection Fraction (LVEF) | 61.5 % of LVEF | Standard Deviation 5.9 |
Secondary
Left Ventricular End-diastolic Volume (LVEDV)
Change in LVEDV after 24 weeks of treatment
Time frame: Baseline, Week 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin Group | Left Ventricular End-diastolic Volume (LVEDV) | 82.2 mL | Standard Deviation 24.7 |
| Control Group | Left Ventricular End-diastolic Volume (LVEDV) | 75.0 mL | Standard Deviation 17.8 |
Secondary
Left Ventricular Mass Index (LVMI)
Change in LVMI after 24 weeks of treatment
Time frame: Baseline, Week 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin Group | Left Ventricular Mass Index (LVMI) | 92.6 g/m2 | Standard Deviation 22.7 |
| Control Group | Left Ventricular Mass Index (LVMI) | 99.1 g/m2 | Standard Deviation 22.5 |
Other Pre-specified
Angiotensin (1-7)
Time frame: Baseline, Week 24
Other Pre-specified
Angiotensin-converting Enzyme 2 (ACE2)
Time frame: Baseline, Week 24
Other Pre-specified
N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP)
Time frame: Baseline, Week 24
Other Pre-specified
Troponin-T
Time frame: Baseline, Week 24