ERtugliflozin triAl in DIabetes With Preserved or Reduced ejeCtion FrAcTion mEchanistic Evaluation in Heart Failure

Phase 2

Completed

• Conditions: Type 2 Diabetes Mellitus; Heart Failure
• Interventions: Drug: Ertugliflozin; Drug: Placebo

• Registration Number: NCT03416270
• Lead Sponsor: University Health Network, Toronto

Brief Summary

This study aims to elucidate the mechanisms whereby the SGLT2i "ertugliflozin" modifies cardiorenal interactions that regulate fluid volume and neurohormonal activation in patients with type 2 diabetes and heart failure (T2D-HF).

Detailed Description

Newer agents called sodium glucose co-transporter-2 inhibitors (SGLT2i) have been developed to improve glycemic control and lower hemoglobin A1c by increasing glycosuria. SGLT2i also reduce blood pressure and albuminuria in T2D - possibly through natriuresis. Importantly, a landmark trial "EMPA-REG OUTCOME" demonstrated that the SGLT2i "empagliflozin" is the first anti- hyperglycemic agent to reduce mortality and HF risk, and also to decrease the risk of progressive diabetic nephropathy. Similar benefits were also recently reported in the CANVAS Program trial with canagliflozin. Despite the benefits observed in these two pivotal trials, the mechanisms responsible for beneficial effects of SGLT2i in patients with T2D with respect to the development and/or worsening of HF are not currently known.

In light of the results of EMPA-REG OUTCOME, the investigators aim to elucidate the mechanisms whereby the SGLT2i "ertugliflozin" modifies cardiorenal interactions that regulate fluid volume and neurohormonal activation in patients with T2D and HF (T2D-HF). The investigators will test the hypothesis that ertugliflozin increases proximal tubular natriuresis, thereby reducing plasma volume, without inducing significant renal vasoconstriction or activation of the sympathetic nervous system (SNS) (see below, Figure 1). The systematic understanding of the effects of SGLT2i in the setting of HF will enable the design of rational physiology based strategies to decrease the burden of HF, which could have major clinical and research implications internationally.

Study Timeline

• Study First Submitted: 2018-01-15
• Study First Submitted QC: 2018-01-23
• Study First Posted: 2018-01-31
• Study Start: 2018-06-28
• Primary Completion: 2021-04-14
• Study Completion: 2021-04-14
• Results First Submitted: 2025-03-07
• Status Verified: 2025-04
• Results First Submitted QC: 2025-04-17
• Last Update Submitted: 2025-04-17
• Results First Posted: 2025-05-06
• Last Update Posted: 2025-05-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 34

Inclusion Criteria

1. Male or female subjects diagnosed with T2D ≥12 months prior to informed consent;
2. eGFR ≥30 ml/min/1.73m2;
3. Age >18 years;
4. HbA1c 6.5%-10.5%;
5. Body Mass Index (BMI) 18.5-45.0 kg/m2;
6. Blood pressure ≤160/110 and ≥90/60 at screening,
7. Heart failure with New York Heart Association (NYHA) class 2-3 symptoms and ejection fraction ≥20%
8. Stable dose of maximally tolerated ACE inhibitor, angiotensin receptor blocker or renin inhibitor for at least 30 days
9. Stable diuretic dose for at least 30 days at the time of baseline physiological assessment
10. BNP levels at baseline ≥100 pg/ml (no atrial fibrillation), ≥200 pg/ml if in atrial fibrillation

Exclusion Criteria

1. Type 1 Diabetes;
2. Leukocyte and/or nitrite positive urinalysis that is untreated;
3. Severe hypoglycaemia within 2 months prior to screening;
4. History of brittle diabetes or hypoglycaemia unawareness based on investigator judgement;
5. Unstable coronary artery disease with acute coronary syndrome, percutaneous intervention or bypass surgery within 3 months;
6. Clinically significant valvular disease;
7. Congestive heart failure secondary to an infiltrative cardiomyopathic process (for example amyloid) or pericardial constriction;
8. Uncontrolled systemic hypertension (systolic blood pressure >160 mmHg and/or diastolic blood pressure >110) or systemic hypotension (systolic blood pressure < 90/60 mmHg);
9. Bariatric surgery or other surgeries that induce chronic malabsorption;
10. Anti-obesity drugs or diet regimen and unstable body weight three months prior to screening;
11. Treatment with systemic corticosteroids;
12. Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells;
13. Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control;
14. Participation in another trial with an investigational drug within 30 days of informed consent;
15. Alcohol or drug abuse within three months prior to informed consent that would interfere with trial participation or any ongoing clinical condition that would jeopardize subject safety or study compliance based on investigator judgement;
16. Liver disease, defined by serum levels of alanine transaminase, aspartate transaminase, or alkaline phosphatase >3 x upper limit of normal as determined during screening;
17. Active malignancy at the time of screening;

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ertuglifozin Treatment Arm	Ertugliflozin	Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) for 12 weeks
Placebo Arm	Placebo	Placebo Matching Ertugliflozin Tablet for 12 weeks

Primary Outcome Measures

Name	Time	Method
Fractional Excretion of Lithium (FELi)	Change in outcomes was measured acute (1 week minus baseline values) and chronic (12 weeks minus baseline values)	The difference in fractional excretion of lithium (FELi) with ertugliflozin vs. placebo. This was measured using exogenous lithium administration 12 hours before lithium excretion was measured in urine and blood.
Fractional Excretion of Sodium (FENa)	Change in outcomes was measured acute (1 week minus baseline values) and chronic (12 weeks minus baseline values)	The difference in fractional excretion of sodium (FENa) with ertugliflozin vs. placebo. This was measured using exogenous lithium administration 12 hours before sodium excretion was measured in urine and blood.
Change in Absolute Fractional Distal Sodium Reabsorption From Baseline (FELi-FENa)	Change in outcomes was measured acute (1 week minus baseline values) and chronic (12 weeks minus baseline values)	The difference in fractional excretion of lithium and fractional excretion of sodium (calculated by the difference between FELi and FENa) with ertugliflozin vs. placebo. This was measured using exogenous lithium administration 12 hours before sodium excretion was measured in urine and blood.

Secondary Outcome Measures

Name	Time	Method
Heart Rate (HR)	chronic (12 weeks)	The difference in seated HR with ertugliflozin vs. placebo
LV Ejection Fraction	chronic (12 weeks)	Echocardiography for markers of systolic and diastolic function
Carotid-femoral Pulse Wave Velocity	chronic (12 weeks)	Arterial Stiffness using SphygmaCor software. Pulse points measured at carotid and femoral arteries.
Plasma Volume	chronic (12 weeks)	Plasma volume will be measured using a non-radioactive technique (indocyanine green dilution)
Extracellular Water	chronic (12 weeks)	Extracellular water will be measured non-invasively using bioimpedence spectroscopy
Cardiac Output	chronic (12 weeks)	Cardiac output will also be measured using non-invasive cardiac monitoring (NICOM)
Systemic Vascular Resistance	chronic (12 weeks)	Systemic vascular resistance will also be measured using non-invasive cardiac monitoring (NICOM)
Blood Angiotensin II	chronic (12 weeks)	Neurohormones/biomarkers
BNP	chronic (12 weeks)	Neurohormones/biomarkers
Norepinephrine	chronic (12 weeks)	Neurohormones/biomarkers
Urinary Adenosine	chronic (12 weeks)	Neurohormones/biomarkers
Glomerular Filtration Rate (GFR)	Glomerular Filtration Rate (GFR, based on plasma iohexol clearance) will be measured at 12 weeks	The difference in iohexol-measured GFR with ertugliflozin vs. placebo. 5ml bolus iohexol (Omnipaque 300mg) was infused intravenously over 2 minutes while participants were supine. Iohexol disappearance curve was used to measure GFR over from 2-4 hours after infusion.
Effective Renal Plasma Flow (ERPF)	Effective Renal Plasma Flow (ERPF, based on paraaminohippurate plasma clearance) will be measured at 12 weeks	The difference in ERPF with ertugliflozin vs. placebo. Paraaminohippurate (PAH) was intravenously administered to measured ERPF.
Systolic Blood Pressure (SBP)	chronic (12 weeks)	The difference in seated SBP with ertugliflozin vs. placebo
Diastolic Blood Pressure (DBP)	chronic (12 weeks)	The difference in seated DBP with ertugliflozin vs. placebo

Trial Locations

Locations (3)

Vanderbilt University Medical Centre; 🇳🇱 Amsterdam, De Boelelaan, Netherlands

University Medical Center Groningen; 🇳🇱 Groningen, Netherlands

Toronto General Hospital; 🇨🇦 Toronto, Ontario, Canada