Cardioprotective Effect of SGLT2-I in Diabetic Patients With AMI (SGLT2-I AMI PROTECT Study)

Diabetes Mellitus Clinical Trial

— SGLT2-I AMI  

Official title:

Cardioprotective Effect of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2-I) in Diabetic Patients With Acute Myocardial Infarction

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05261867
• Other study ID #: SGLT2I001
• Status: Recruiting
• Start date: January 2017
• Est. completion date: January 2023

Study information

• Verified date: October 2022
• Source: IRCCS Azienda Ospedaliero-Universitaria di Bologna
• Contact: Carmine Pizzi, MD
• Email: carmine.pizzi[@]unibo.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Despite their potential benefits on the heart with pleiotropic mechanisms, the cardioprotective effects of new glucose-lowering SGLT-2 inhibitors in patients with myocardial infarction - both in the acute and chronic phase - have never been explored. The key point of the project will be the evaluation of the cardioprotective effect and the potential prognostic benefit of SGLT-2 inhibitors in patients with diabetes and acute myocardial infarction.

Description:

Classically, the physiopathology of myocardial infarction is linked to the presence of coronary atherosclerosis. According to the European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines of the fourth Universal definition, type 1 myocardial infarction (MI), the most frequent cause was atherothrombotic plaque (the mechanism of plaque erosion, rupture, fissuring with an athero-thrombotic)(1) In acute myocardial infarction, early restoration of epicardial and myocardial blood flow is of paramount importance to limit infarction size and create optimum conditions for favorable long-term outcome. Currently, restoration of epicardial blood flow is preferably and effectively obtained by primary percutaneous coronary intervention (PPCI). After opening the occluded artery, however, the reperfusion process itself causes damage to the myocardium, the so called "reperfusion injury". The phenomenon of reperfusion injury is incompletely understood and currently there is no established therapy for preventing it. Contributory factors are intramyocardial edema with compression of the microvasculature, oxidative stress, calcium overload, mitochondrial transition pore opening, micro embolization, neutrophil plugging and hyper contracture. This results in myocardial stunning, reperfusion arrhythmias and ongoing myocardial necrosis (2,3). There is general agreement that a large part of the cell death caused by myocardial reperfusion injury occurs during the first few minutes of reperfusion, and that early treatment is required to prevent it. According to current guidelines, drug therapy administrated for acute myocardial infarction includes antiplatelets (against atherosclerotic plaque and stent thrombosis), renin-angiotensin-aldosterone system (RAAS) inhibitors, beta-blockers and lipid-lowering therapy (primarily with statins). Due to their high efficacy, excellent tolerability, and their ability to reduce major adverse cardiovascular events in large clinical trials, SGLT2 inhibitors have been tested in a variety of preclinical studies and it was demonstrated to reduce acute myocardial ischemia-reperfusion (I/R) injury (4). Four-week pre-treatment with dapagliflozin could decrease infarct size in rats with obese insulin resistance which underwent cardiac ischemic-reperfusion injury (5) and a recent experimental study demonstrated that acute dapagliflozin administration during cardiac I/R injury exerted cardioprotective effects by attenuating cardiac infarct size, increasing left ventricular function and reducing arrhythmias (6). Moreover, in rats with previous myocardial infarct, dapagliflozin treatment beginning one day after left anterior descending coronary artery ligation could decrease myofibroblast infiltration and myocardial fibrosis (7). Finally, a preregistered meta-analysis (PROSPERO), that included placebo-controlled, interventional studies of small and large animal models of myocardial ischaemia-reperfusion injury, testing the effect of SGLT2 inhibitor treatment on myocardial infarct size concluded that the glucose-lowering SGLT2 inhibitors reduce myocardial infarct size in animal models independent of diabetes status (8). Despite its potential benefits on the heart with pleiotropic mechanisms, the cardioprotective effects of new glucose-lowering SGLT-2 inhibitors in patients with myocardial infarction - both in the acute and chronic phase- have never been explored. The key point of the project will be the evaluation of the cardioprotective effect and the potential prognostic benefit of SGLT-2 inhibitors in patients with diabetes and acute myocardial infarction. The investigators' findings could provide significant insights for future clinical trials on SGLT-2 inhibitors treatments in patients with ischemic heart disease.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 800
• Est. completion date: January 2023
• Est. primary completion date: November 2021
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age =18 y old
• STEMI/NSTEMI diagnosed according to ESC guidelines undergoing reperfusion treatment with percutaneous transluminal coronary angioplasty (PTCA).
• Known type II diabetes mellitus treated with oral antidiabetic drugs

Exclusion Criteria:

• Type I diabetes mellitus or type II diabetes mellitus treated only with insulin therapy alone or in combination with other anti-diabetic drugs.
• Patients treated with Coronary artery bypass grafting (CABG) after the coronary angiography (CAG) (NSTEMI)
• Previous CABG
• Severe valvular heart disease.
• Contraindications for secondary medical prevention therapy approved for myocardial infarctions, like beta-blockers, angiotensin-converting enzyme inhibitor(ACEI )/angiotensin receptor blocker (ARBs), antiplatelets, statins. All patients will be treated with optimal secondary prevention therapy suggested by the current ESC guidelines.
• Patients who start SGLT2 therapy after the acute index event.

Related Conditions & MeSH terms

• Acute Coronary Syndrome
• Diabetes Mellitus

Locations

Country	Name	City	State
Belgium	Cardiovascular Center Aalst, OLV-Clinic, Aalst, Belgium	Aalst
Bulgaria	Alexandrovska University Hospital, Sofia, Bulgaria	Sofia
Italy	Policlinico Sant'Orsola	Bologna
Italy	Azienda Ospedaliera Sant'Anna e San Sebastiano, Caserta	Caserta
Italy	ASST Grande Ospedale Metropolitano Niguarda, Milano	Milan
Italy	Università Vanvitelli, Ospedale Cardarelli, Napoli	Napoli
Italy	Azienda Ospedaliero-Universitaria Sant'Andrea, Roma	Roma

Sponsors (10)

Lead Sponsor	Collaborator
IRCCS Azienda Ospedaliero-Universitaria di Bologna	Alexandrovska University Hospital, ASST Grande Ospedale Metropolitano Niguarda, Azienda Ospedaliera "Sant'Andrea", Azienda Ospedaliera Sant'Anna e San Sebastiano, Cardarelli Hospital, Maggiore Hospital Carlo Alberto Pizzardi, Niguarda Hospital, University of Campania "Luigi Vanvitelli", VZW Cardiovascular Research Center Aalst

Countries where clinical trial is conducted

Belgium,  Bulgaria,  Italy, 

References & Publications (7)

Andreadou I, Bell RM, Bøtker HE, Zuurbier CJ. SGLT2 inhibitors reduce infarct size in reperfused ischemic heart and improve cardiac function during ischemic episodes in preclinical models. Biochim Biophys Acta Mol Basis Dis. 2020 Jul 1;1866(7):165770. doi — View Citation

Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest. 2013 Jan;123(1):92-100. doi: 10.1172/JCI62874. Epub 2013 Jan 2. Review. — View Citation

Lahnwong S, Palee S, Apaijai N, Sriwichaiin S, Kerdphoo S, Jaiwongkam T, Chattipakorn SC, Chattipakorn N. Acute dapagliflozin administration exerts cardioprotective effects in rats with cardiac ischemia/reperfusion injury. Cardiovasc Diabetol. 2020 Jun 15 — View Citation

Lee TM, Chang NC, Lin SZ. Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med. 2017 Mar;104:298-310. doi: 10.1016/j.freeradbiome — View Citation

Sayour AA, Celeng C, Oláh A, Ruppert M, Merkely B, Radovits T. Sodium-glucose cotransporter 2 inhibitors reduce myocardial infarct size in preclinical animal models of myocardial ischaemia-reperfusion injury: a meta-analysis. Diabetologia. 2021 Apr;64(4): — View Citation

Tanajak P, Sa-Nguanmoo P, Sivasinprasasn S, Thummasorn S, Siri-Angkul N, Chattipakorn SC, Chattipakorn N. Cardioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia-reperfusion injury. J Endocrinol. 2018 Feb;236(2):69-84. doi: 10.153 — View Citation

Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite of cardiovascular death, recurrent AMI, and hospitalization for HF (MACE).	Composite of cardiovascular death, recurrent AMI, and hospitalization for HF (MACE).	Through study completion, an average of 2 year
Secondary	Intra-hospital cardiovascular death	Intra-hospital cardiovascular death mortality included deaths that result from an AMI, sudden cardiac death, heart failure, stroke, and other cardiovascular causes during the hospitalization.	Up to 30 days
Secondary	Intra-hospital atrial and ventricular arrhythmias	Ventricular arrhythmias were defined as a cardiac arrhythmia of three or more consecutive complexes originating from the ventricles at a rate of greater than 100 beats per minute. We included both sustained (lasting 30 sec or more) and non-sustained (lasting less than 30 sec) ventricular arrhythmias due to similar risk of adverse cardiovascular outcomes associated with both these types.	Up to 30 days
Secondary	Reduction of the infarct size	Myocardial infarct size was estimated using high-sensitivity troponin (at the moment of hospital admission and every 3-6 hours thereafter for the following 24 hours) and the left ventricular end-diastolic volume (LVEDV) and the biplane left ventricular ejection fraction (LVEF).	Up to 30 days
Secondary	Reduction of the inflammatory response.	The inflammatory response was evaluated using the following parameters: C reactive protein (CRP), white blood cells - leukocytes and neutrophils count, neutrophil to lymphocyte ratio (NLR), neutrophil to platelet ratio (NPR), platelet to lymphocytes ratio (PLR), C-Reactive Protein. In particular, NLR is the ratio of neutrophil and lymphocyte counts, NPR is the ratio of neutrophil and platelet counts, and PLR is obtained by dividing the platelet count by the lymphocytes. Patients with concomitant basal values of CRP and NLR above the median were considered to have an inflammatory response.	Up to 30 days
Secondary	Contrast-induced acute kidney injury	Contrast-induced acute kidney injury is defined as an increase in sCr by 0.3 mg/dL or an increase in creatinine to ?1.5 times baseline within 3 to 5 days following contrast exposure.	Through study completion, an average of 1 year
Secondary	Length of hospital stay	Length of hospitalization (days)	Up to 30 days
Secondary	All-cause mortality	All-cause mortality included all causes of death for the population during the follow-up.	Through study completion, an average of 2 year
Secondary	Cardiovascular mortality	Cardiovascular death consisted of deaths that result from an AMI, sudden cardiac death, heart failure, stroke, and other cardiovascular causes.	Through study completion, an average of 2 year.
Secondary	Heart failure hospitalization.	Heart failure re-hospitalization was evaluated according to the ESC Guidelines and consisted of unscheduled hospital admission for a primary diagnosis of HF in which the patient presented typical signs, symptoms, and diagnostic testing consistent with the diagnosis of HF and consequently received HF-directed therapy.	Through study completion, an average of 2 year.
Secondary	Recurrent AMI	Recurrent acute myocardial infarction.	Through study completion, an average of 2 year
Secondary	Any coronary revascularization	Clinically indicated target vessel revascularization for significant renarrowing.	Through study completion, an average of 2 year