Targeting epicardial adipose tissue: A potential therapeutic strategy for heart failure with preserved ejection fraction with type 2 diabetes mellitus

Table 3 Pharmacological interventions targeting epicardial adipose tissue

Ref.	Imaging method	Participants, n	Intervention method and duration	Change of EAT	Other findings
Park et al[74], 2010	Echo	145 coronary artery stenosis patients	Atorvastatin: n = 82, 20 mg/d; simvastatin: n = 63, 10 mg/d; for 6-8 mo	Atorvastatin decreased EAT thickness (0.47 ± 0.65 mm) more than simvastatin (EAT 0.12 ± 0.52 mm, P = 0.001)	Decreased TC, TG, and LDL-C
Soucek et al[75], 2015	CT	38 atrial fibrillation patients	Atorvastatin: 80 mg/d, for 3 mo	EAT volume decreased from 86.9 (64.1-124.8) mL to 92.3 (62.0- 133.3) mL (P < 0.05)	Decreased CRP, TC, and LDL-C
Alexopoulos et al[76], 2013	CT	420 hyperlipidemic post-menopausal women	Atorvastatin: n = 194, 80 mg/d; pravastatin: n = 226, 40 mg/d; for 12 mo	Atorvastatin decreased EAT volume (3.38%) more than pravastatin (0.83%, P = 0.025)	Decreased TC, TG, and LDL-C
Rivas Galvez et al[78], 2020	Echo	41 patients treated with PCSK9 inhibitors	Evolocumab: n = 16; alirocumab: n = 8; twice in 6 mo	EAT thickness decreased by 20.39% (P = 0.0001).	Decreased BMI, TC, and LDL-C
Iacobellis et al[82], 2017	Echo	41 patients T2DM	Metformin: 500 mg-1000 mg, twice daily, for 6 mo	EAT thickness changed from 7.4 ± 1.6 mm to 7.5 ± 1.5 mm and 6.9 ± 1.3 mm at 3 and 6 mo, respectively	Decreased BMI
Ziyrek et al[83], 2019	Echo	40 T2DM patients	Metformin: 1000 mg, twice daily, for 3 mo	EAT thickness decreased from 5.07 ± 1.33 mm to 4.76 ± 1.32 mm (P < 0.001)
Iacobellis et al[84], 2020	Echo	51 T2DM patients	Metformin: 500 mg-1000 mg, twice daily, for 6 mo	EAT thickness decreased from 8.0 ± 2.5 mm to 7.4 ± 2.5 mm and 7.5 ± 2.4 mm at 3 and 6 mo, respectively (compared with baseline P < 0.016)
Moody et al[90], 2014	CMR	12 T2DM patients	Pioglitazone: 15 mg/d, for 2 wk, then increase to 45 mg/d, for 22 wk	EAT area decreased from 15.3 ± 3.9 cm2 to 14.0 ± 3.9 cm2 (P = 0.03)	Decreased paracardial adipose tissue; improved left ventricular diastolic function
Lima-Martínez et al[94], 2015	Echo	26 T2DM patients	Combination of sitagliptin (50 mg) and metformin (1000 mg), twice daily, for 24 wk	EAT thickness reduction of 15% (P = 0.001)
van Eyk et al[99], 2019	CMR	22 T2DM patients	Liraglutide: 0.6 mg/d gradually increased to 1.8 mg/d in 2 wk, for 26 wk	EAT area reduction of 0 ± 2 cm2	Decreased visceral fat volume
Bizino et al[100], 2020	CMR	23 T2DM patients	Liraglutide: 0.6 mg/d gradually increased to 1.8 mg/d in 2 wk, 26 wk	EAT area reduction of 1.1 ± 6.0 cm2	Decreased body weight and subcutaneous fat
Iacobellis et al[82], 2017	Echo	54 T2DM patients	Combination of liraglutide (increased to 1.8 mg/once daily) and metformin (1000 mg, twice daily), for 12 wk	EAT thickness reduction of 29% and 36% at 3 and 6 mo, respectively	Decreased BMI and HbA1c
Zhao et al[101], 2021	Echo	21 T2DM patients	Liraglutide: 0.6 mg/d gradually increased to 1.2 mg/d in 3-5 d, for 3 mo	EAT decreased from 5.00 (5.0-7.0) mm to 3.95 ± 1.43 mm (P < 0.001)	Decreased weight, HbA1c, TC, TG, and LDL-C
Dutour et al[102], 2016	CMR	22 T2DM patients	Exenatide: 5 mg twice daily, for 4 wk, then increase to 10 mg twice daily, for 22 wk	EAT volume reduction of 8.8 ± 2.1%	Decreased weight, HbA1c, and hepatic triglyceride content
Morano et al[103], 2015	Echo	25 T2DM patients	Combination of exenatide (5 mg twice daily, for 1 mo, and then increase to 10 mg twice daily, for 2 mo) and liraglutide (1.2 mg/d), for 3 mo	EAT thickness decreased from 9.4 ± 1.6 mm to 8.0 ± 1.9 mm (P = 0.003)	Decreased MRI; improved renal resistive index
Iacobellis et al[104], 2020	Echo	6 T2DM patients	Semaglutide: n = 30, 1 mg weekly; dulaglutide: n = 30, 1.5 mg weekly; for 12 wk	EAT thickness reduction of 20% in both semaglutide and dulaglutide groups	Decreased BMI and HbA1c
Requena et al[108], 2021	CMR	84 non-diabetic patients with HFrEF	Empagliflozin: 10 mg/d, for 6 mo	EAT volume reduction of 5.14 mL, P < 0.05	Decreasing subcutaneous fat and matrix volume
Ardahanlı et al[109], 2021	Echo	37 T2DM patients	Empagliflozin: 10 mg/d, for 6 mo	EAT thickness decreased from 7.6 ± 1.7 mm to 6.7 ± 1.3 mm (P < 0.001)	Decreased BMI, waist circumference, HbA1c, uric acid, systolic and diastolic blood pressure, and carotid intima-media thickness
Iacobellis et al[84], 2020	Echo	51 T2DM patients	Combination of dapagliflozin (5 to 10 mg/d) and metformin (500 to 1000 mg, twice daily), for 24 mo	EAT thickness decreased by 15% from baseline to 12 wk and 20% after 24 wk (compared with baseline P < 0.01)	Decreased weight and HbA1c
Sato et al[110], 2018	CT	20 T2DM patients	Dapagliflozin: 10 mg/d, for 6 mo	EAT volume reduction of 16.4 ± 8.3 mL (P < 0.05)	Decreased HbA1c, TNF-α, TG, insulin resistance, and left atrial dimension
Sato et al[111], 2020	CT	18 T2DM patients with coronary artery disease	Dapagliflozin: 5 mg/d, for 6 mo	EAT volume reduction of 15.2 ± 12.8 mL (P < 0.05)	Decreased HbA1c, TNF-α, and insulin resistance
Braha et al[112], 2021	CT	52 T2DM patients	Dapagliflozin: 10 mg/d, for 6 mo	EAT volume reduction of 17.1% (P < 0.001)	Decreased BMI, triglyceride glucose index, and HbA1c
Yagi et al[113], 2017	Echo	13 T2DM patients	Canagliflozin: 100 mg/d, for 6 mo	EAT thickness decreased from 9.3 ± 2.5 to 8.1 ± 2.3 mm (P < 0.01) and to 7.3 ± 2.0 mm (P < 0.001) at 3 mo and 6 mo, respectively	Decreased BMI
Fukuda et al[114], 2017	CMR	9 T2DM patients	Ipragliflozin: 50 mg/d, 12 wk	EAT volume decreased from 102 (79-126) mL to 89 (66-109) mL (P = 0.008)	Decreased weight, BMI, HbA1c, TG, leptin, fasting plasma glucose, and insulin resistance
Bouchi et al[115], 2017	CMR	19 T2DM patients	Luseogliflozin: 2.5-5.0 mg/d for 12 wk	EAT volume decreased from 117 (96-136) mL to 111 (88-134) mL (P = 0.048)	Decreased weight, BMI, systolic and diastolic blood pressure, HbA1c, fasting plasma glucose, insulin resistance, and CRP
Gaborit et al[116], 2021	CMR	26 T2DM patients	Empagliflozin: 10 mg/d, 12 wk	EAT volume decreased from 108.5 ± 31.8 mL to 106.9 ± 31.8 mL (P = 0.09)	Decreased BMI, TG, HbA1c, fasting blood glucose, liver fat content, and visceral fat volume

BMI: Body mass index; CMR: Cardiovascular magnetic resonance; CRP: C-reactive protein; CT: Computed tomography; EAT: Epicardial adipose tissue; Echo: Echocardiography; HbA1c: Glycosylated hemoglobin; HFrEF: Heart failure with reduced ejection fraction; LDL-C: Low-density lipoprotein cholesterol; MRI: Magnetic resonance imaging; PCSK9: Proprotein convertase subtilisin/kexin type 9; T2DM: Type 2 diabetes mellitus; TC: Total cholesterol; TG: Triglycerides; TNF-α: Tumor necrosis factor-α.