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

NCT ID: NCT05261867

Last Updated: 2022-10-24

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 800 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2017-01-31
• Study Completion Date: 2023-01-31

Brief 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.

Detailed 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.

Conditions

Diabetes Mellitus; Acute Coronary Syndrome

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: RETROSPECTIVE

Study Groups

Diabetic patients treated with SGLT2-I

Diabetic patients treated with SGLT2-I alone or in combination with other oral anti-diabetic (OAD) agents. Patients were considered in the SGLT2-I group if it was started at least 1 month prior to index hospitalization.

No interventions assigned to this group

Diabetic patients treated with other oral anti-diabetic (OAD) agents

Diabetic patients treated with other oral anti-diabetic agents alone.

No interventions assigned to this group

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Maggiore Hospital Carlo Alberto Pizzardi

OTHER

Sponsor Role: collaborator

VZW Cardiovascular Research Center Aalst

OTHER

Sponsor Role: collaborator

Cardarelli Hospital

OTHER

Sponsor Role: collaborator

Azienda Ospedaliera Sant'Anna e San Sebastiano

OTHER

Sponsor Role: collaborator

Azienda Ospedaliera "Sant'Andrea"

OTHER

Sponsor Role: collaborator

Alexandrovska University Hospital

OTHER

Sponsor Role: collaborator

Niguarda Hospital

OTHER

Sponsor Role: collaborator

University of Campania Luigi Vanvitelli

OTHER

Sponsor Role: collaborator

ASST Grande Ospedale Metropolitano Niguarda

OTHER

Sponsor Role: collaborator

IRCCS Azienda Ospedaliero-Universitaria di Bologna

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Cardiovascular Center Aalst, OLV-Clinic, Aalst, Belgium

Aalst, , Belgium

Site Status: RECRUITING

Alexandrovska University Hospital, Sofia, Bulgaria

Sofia, , Bulgaria

Site Status: RECRUITING

Policlinico Sant'Orsola

Bologna, , Italy

Site Status: RECRUITING

Azienda Ospedaliera Sant'Anna e San Sebastiano, Caserta

Caserta, , Italy

Site Status: RECRUITING

ASST Grande Ospedale Metropolitano Niguarda, Milano

Milan, , Italy

Site Status: RECRUITING

Università Vanvitelli, Ospedale Cardarelli, Napoli

Napoli, , Italy

Site Status: RECRUITING

Azienda Ospedaliero-Universitaria Sant'Andrea, Roma

Roma, , Italy

Site Status: RECRUITING

Countries

Belgium; Bulgaria; Italy

Central Contacts

Carmine Pizzi, MD

Role: CONTACT

carmine.pizzi@unibo.it

Pizzi Carmine, MD

Role: CONTACT

carmine.pizzi@unibo.it

Facility Contacts

Emanuele Barbato, MD

Role: primary

Niya Mileva, MD

Role: primary

Carmine Pizzi

Role: primary

carmine.pizzi@unibo.it

Paolo Calabrò, MD

Role: primary

Jacopo Andrea Oreglia, MD

Role: primary

Raffaele Marfella, MD

Role: primary

Giuliano Tocci, MD

Role: primary

References

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 Force for the Universal Definition of Myocardial Infarction. Fourth Universal Definition of Myocardial Infarction (2018). Circulation. 2018 Nov 13;138(20):e618-e651. doi: 10.1161/CIR.0000000000000617. No abstract available.

Reference Type: RESULT

PMID: 30571511 (View on PubMed)

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.

Reference Type: RESULT

PMID: 23281415 (View on PubMed)

Andreadou I, Bell RM, Botker 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: 10.1016/j.bbadis.2020.165770. Epub 2020 Mar 17.

Reference Type: RESULT

PMID: 32194159 (View on PubMed)

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: 10.1530/JOE-17-0457. Epub 2017 Nov 15.

Reference Type: RESULT

PMID: 29142025 (View on PubMed)

Lahnwong C, 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;19(1):91. doi: 10.1186/s12933-020-01066-9.

Reference Type: RESULT

PMID: 32539724 (View on PubMed)

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.freeradbiomed.2017.01.035. Epub 2017 Jan 26.

Reference Type: RESULT

PMID: 28132924 (View on PubMed)

Sayour AA, Celeng C, Olah 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):737-748. doi: 10.1007/s00125-020-05359-2. Epub 2021 Jan 23.

Reference Type: RESULT

PMID: 33483761 (View on PubMed)

Paolisso P, Bergamaschi L, Gragnano F, Gallinoro E, Cesaro A, Sardu C, Mileva N, Foa A, Armillotta M, Sansonetti A, Amicone S, Impellizzeri A, Esposito G, Morici N, Andrea OJ, Casella G, Mauro C, Vassilev D, Galie N, Santulli G, Marfella R, Calabro P, Pizzi C, Barbato E. Outcomes in diabetic patients treated with SGLT2-Inhibitors with acute myocardial infarction undergoing PCI: The SGLT2-I AMI PROTECT Registry. Pharmacol Res. 2023 Jan;187:106597. doi: 10.1016/j.phrs.2022.106597. Epub 2022 Dec 5.

Reference Type: DERIVED

PMID: 36470546 (View on PubMed)

Cesaro A, Gragnano F, Paolisso P, Bergamaschi L, Gallinoro E, Sardu C, Mileva N, Foa A, Armillotta M, Sansonetti A, Amicone S, Impellizzeri A, Esposito G, Morici N, Oreglia JA, Casella G, Mauro C, Vassilev D, Galie N, Santulli G, Pizzi C, Barbato E, Calabro P, Marfella R. In-hospital arrhythmic burden reduction in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: Insights from the SGLT2-I AMI PROTECT study. Front Cardiovasc Med. 2022 Sep 27;9:1012220. doi: 10.3389/fcvm.2022.1012220. eCollection 2022.

Reference Type: DERIVED

PMID: 36237914 (View on PubMed)

Paolisso P, Bergamaschi L, Santulli G, Gallinoro E, Cesaro A, Gragnano F, Sardu C, Mileva N, Foa A, Armillotta M, Sansonetti A, Amicone S, Impellizzeri A, Casella G, Mauro C, Vassilev D, Marfella R, Calabro P, Barbato E, Pizzi C. Infarct size, inflammatory burden, and admission hyperglycemia in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: a multicenter international registry. Cardiovasc Diabetol. 2022 May 15;21(1):77. doi: 10.1186/s12933-022-01506-8.

Reference Type: DERIVED

PMID: 35570280 (View on PubMed)

Other Identifiers

SGLT2I001

Identifier Type: -

Identifier Source: org_study_id