Clinical trial NCT03485222: Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity? (ATRU-4).
Official title: EMPA-TROPISM Trial: Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity?
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cardiovascular Diseases
Keywords: Cardiovascular diseases
Heart Failure
LV remodeling
SGLT-2 Inhibitors
Empagliflozin
Cardiac MRI
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
Collaborators: name: Boehringer Ingelheim
name: Eli Lilly and Company
First posted: 2018-04-02
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Purpose:

The overall hypothesis of the study is that the benefits attained in the EMPA-OUTCOME were, at least in part, mediated by a glucose-independent mechanism. Thus, to demonstrate the existence of the postulated non-glucose dependent effects, the researchers will investigate the safety and efficacy of empagliflozin versus placebo on top of guideline-directed medical therapy in heart failure patients with reduced ejection fraction without diabetes.

Detailed description: Heart failure (HF) is a frequent co-morbid condition associated with poor prognosis in diabetes, particularly among older patients. HF accounts for more than 1 Million hospitalizations annually in USA. In addition, HF hospitalizations are associated with significant high risk of post-discharge mortality and recurrent hospitalizations. Almost one-half of patients will be re-hospitalized within 6 months and one-third will die within 12 months of discharge. Median survival after HF diagnosis is about 5 years and is similar for HFpEF and heart failure with reduced ejection fraction (HFrEF) patients. Diabetes as co-morbidity multiplies risk of hospital admissions in HF patients.

Type 2 Diabetes Mellitus (T2DM) is a pathological condition characterized by elevated glucose levels and it is associated with high incidence of cardiovascular (CV) events. Several hypoglycemic agents have successfully managed the elevated glucose levels but with little or no impact on CV events. Management of concomitant HF in T2DM is particularly challenging, as some glucose-lowering agents, such as TZDs, are contraindicated in the treatment of HF patients. Thus, there was a need for an oral agent that improved glycemia as well as provided CV benefits. Empagliflozin is the first glucose-lowering agent showing that not only improves glycemic control but also has cardiovascular benefits. The recent EMPA-OUTCOME trial has shown significant reductions in major adverse cardiac events (MACE), cardiovascular mortality, and hospitalization for Heart Failure (HF) by Empagliflozin given on top of standard-of-care therapy for T2DM patients with Cardiovascular disease (CVD). The dramatic change driving the superiority of the primary composite outcome was a significantly lower CV death rate (38% relative risk reduction). In addition, there were also an impressive 35% and 38% relative risk reductions in hospitalization for heart failure (HF) and death from any cause, respectively.

Empagliflozin is a member of a new class of hypoglycemic agents, the SGLT-2 inhibitors. There are a couple of characteristics that single out the SGLT2 inhibitors from other hypoglycemic drugs. One is their low hypoglycemic risk since they act on the urinary excretion of glucose without interfering with the physiologic response to hypoglycemia. And the other is their "positive" cardiovascular effects such as lowering blood pressure, arterial stiffness, urinary microalbuminuria and triglycerides while increasing HDL-Cholesterol levels. Therefore, the combination of the above-mentioned observations led to some investigators to suggest that these benefits may be, at least in part, independent of its hypoglycemic activity and thus, Empagliflozin could be considered a "cardiac" drug.

Eligibility criteria: Inclusion Criteria:

* Patients should meet the following inclusion criteria:
* Ambulatory patients age 18-85 years
* Diagnosis of Heart failure (NYHA II to III)
* LVEF\<50% on echocardiography or CMRI in the previous 6 months
* Have stable symptoms and therapy for HF within the last 3 months.

Exclusion Criteria:

* Pregnant or lactating women.
* Any history of diabetes by medical history or by any of the established criteria by the American Diabetes Association. It also includes patients with history of diabetes in remission.
* ACS or cardiac surgery within the last 3 months.
* Cancer or any other life-threatening condition.
* Pancreatitis.
* Glomerular Filtration Rate \< 45 ml/Kg/min.
* Use of continuous parental inotropic agents.
* Systolic BP \< 90 mm Hg.
* Psychiatric disease incompatible with being in study.
* Any contraindication to MRI procedures.
* Any other medical or physical condition considered to be inappropriate by a study physician.

Primary outcomes:
measure: Change in Left Ventricle-end Systolic Volume (ESV)
timeFrame: Baseline and 6 months
measure: Change in LV-end Diastolic Volume (EDV)
timeFrame: Baseline and 6 months
Secondary outcomes:
measure: Change in LV-Ejection Fraction Index
timeFrame: Baseline and 6 months
measure: Change in VO2 Consumption
timeFrame: Baseline and 6 months
measure: Change in 6 Min Walk Test
timeFrame: Baseline and 6 months
measure: Change in Kansas Cardiomyopathy Questionnaire (KCCQ-12)
timeFrame: Baseline and 6 months
Other outcomes:
Locations:
city: New York
country: United States
facility: Mount Sinai Heart - Icahn School of Medicine at Mount Sinai
state: New York
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Juan J Badimon, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, Garcia-Ropero A, Mancini D, Pinney S, Macaluso F, Sartori S, Roque M, Sabatel-Perez F, Rodriguez-Cordero A, Zafar MU, Fergus I, Atallah-Lajam F, Contreras JP, Varley C, Moreno PR, Abascal VM, Lala A, Tamler R, Sanz J, Fuster V, Badimon JJ; EMPA-TROPISM (ATRU-4) Investigators. Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction. J Am Coll Cardiol. 2021 Jan 26;77(3):243-255. doi: 10.1016/j.jacc.2020.11.008. Epub 2020 Nov 13.
citation: Kanie T, Mizuno A, Takaoka Y, Suzuki T, Yoneoka D, Nishikawa Y, Tam WWS, Morze J, Rynkiewicz A, Xin Y, Wu O, Providencia R, Kwong JS. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis. Cochrane Database Syst Rev. 2021 Oct 25;10(10):CD013650. doi: 10.1002/14651858.CD013650.pub2.
citation: Requena-Ibanez JA, Santos-Gallego CG, Rodriguez-Cordero A, Vargas-Delgado AP, Mancini D, Sartori S, Atallah-Lajam F, Giannarelli C, Macaluso F, Lala A, Sanz J, Fuster V, Badimon JJ. Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF: From the EMPA-TROPISM Study. JACC Heart Fail. 2021 Aug;9(8):578-589. doi: 10.1016/j.jchf.2021.04.014.