Clinical trial NCT05261867: Cardioprotective Effect of SGLT2-I in Diabetic Patients With AMI (SGLT2-I AMI PROTECT Study)
Official title: Cardioprotective Effect of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2-I) in Diabetic Patients With Acute Myocardial Infarction
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Diabetes Mellitus
Acute Coronary Syndrome
Keywords: SGLT2-I
Acute myocardial infarction
Diabetes Mellitus
Prognosis
Lead sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna
Sponsor class: OTHER
Collaborators: name: Maggiore Hospital Carlo Alberto Pizzardi
name: VZW Cardiovascular Research Center Aalst
name: Cardarelli Hospital
name: Azienda Ospedaliera Sant'Anna e San Sebastiano
name: Azienda Ospedaliera "Sant'Andrea"
name: Alexandrovska University Hospital
name: Niguarda Hospital
name: University of Campania Luigi Vanvitelli
name: ASST Grande Ospedale Metropolitano Niguarda
First posted: 2022-03-02
Enrollment: 800
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Consecutive patients with STEMI/NSTEMI diagnosed according to ESC guidelines undergoing reperfusion treatment with percutaneous transluminal coronary angioplasty (PTCA) with known type II diabetes mellitus treated with oral antidiabetic drugs.

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.

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.

Primary outcomes:
measure: Composite of cardiovascular death, recurrent AMI, and hospitalization for HF (MACE).
timeFrame: Through study completion, an average of 2 year
Secondary outcomes:
measure: Intra-hospital cardiovascular death
timeFrame: Up to 30 days
measure: Intra-hospital atrial and ventricular arrhythmias
timeFrame: Up to 30 days
measure: Reduction of the infarct size
timeFrame: Up to 30 days
measure: Reduction of the inflammatory response.
timeFrame: Up to 30 days
measure: Contrast-induced acute kidney injury
timeFrame: Through study completion, an average of 1 year
measure: Length of hospital stay
timeFrame: Up to 30 days
measure: All-cause mortality
timeFrame: Through study completion, an average of 2 year
measure: Cardiovascular mortality
timeFrame: Through study completion, an average of 2 year.
measure: Heart failure hospitalization.
timeFrame: Through study completion, an average of 2 year.
measure: Recurrent AMI
timeFrame: Through study completion, an average of 2 year
measure: Any coronary revascularization
timeFrame: Through study completion, an average of 2 year
Other outcomes:
Locations:
city: Aalst
country: Belgium
facility: Cardiovascular Center Aalst, OLV-Clinic, Aalst, Belgium
city: Sofia
country: Bulgaria
facility: Alexandrovska University Hospital, Sofia, Bulgaria
city: Bologna
country: Italy
facility: Policlinico Sant'Orsola
city: Caserta
country: Italy
facility: Azienda Ospedaliera Sant'Anna e San Sebastiano, Caserta
city: Milan
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda, Milano
city: Napoli
country: Italy
facility: Università Vanvitelli, Ospedale Cardarelli, Napoli
city: Roma
country: Italy
facility: Azienda Ospedaliero-Universitaria Sant'Andrea, Roma
Study officials:
References:
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 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.
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.
citation: 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.
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: 10.1530/JOE-17-0457. Epub 2017 Nov 15.
citation: 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.
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.freeradbiomed.2017.01.035. Epub 2017 Jan 26.
citation: 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.
citation: 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.
citation: 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.