Insights into SGLT2 inhibitor treatment of diabetic cardiomyopathy: focus on the mechanisms

Huang, Keming; Luo, Xianling; Liao, Bin; Li, Guang; Feng, Jian

doi:10.1186/s12933-023-01816-5

Cardiovascular Diabetology

Table 1 Therapeutic targets of SGLT2i in basic science trials

From: Insights into SGLT2 inhibitor treatment of diabetic cardiomyopathy: focus on the mechanisms

Drug	Target	Organ or tissue	Model	Effect
Empagliflozin	GLUT1	Heart	Isolated failing human and murine cardiomyocytes	Improve glucose metabolism [1]
Empagliflozin	HMGCS2	Liver, kidney and jejunum	Normal and db/db mice	Increase serum ketone bodies [2]
Empagliflozin	CPT1b	Heart	Otsuka long-evans tokushima fatty rats	Reduce fatty acid utilization [3]
Empagliflozin	PPARγ/CD36	Heart	Zucker diabetic fatty rats	Reduce the accumulation of fatty acids [4]
Canagliflozin	PPAR-α	Adipose tissue	Obese mice due to a high-fat diet	Decrease plasma TG and TC [5]
Dapagliflozin	Drp1	Heart	High-fat diet-induced insulin-resistant obesity rats	Inhibit mitochondrial fission [6]
Dapagliflozin, Empagliflozin	MFN1/MFN2 and OPA1	Heart	Metabolic syndrome rats; high-fat diet/STZ-induced diabetic rats	Inhibit mitochondrial fission [7, 8]
Empagliflozin	PGC-1a, NRF-1 and mtTFA	Heart	High-fat diet/STZ-induced diabetic rats	Promote mitochondrial biogenesis [8]
Empagliflozin, Dapagliflozin, Canagliflozin	ETC complex I and II	Human RPTEC/TERT1 cells	Normal	Improve the activity of ETC complex I and II (Canagliflozin reduce the activity of ETC complex I) [9]
Dapagliflozin	O-GlcNAc transferase	Kidney	STZ-induced diabetic rats	May improve the activity of ETC complexes [10]
Empagliflozin	Phenotype polarization of macrophages	The aorta	Mouse model of atherosclerosis with diabetes	Reduce atherosclerosis [11, 12]
Empagliflozin	AT1R and ACE	Coronary artery endothelium	High glucose-treated porcine coronary artery	Delay endothelial cell senescence [13]
Luseogliflozin	GLUT9 isoform 2	Xenopus laevis oocytes	Cells were injected with 0.1–25 ng of cRNA of GLUT9 isoform 2	Reduce uric acid [14]
Empagliflozin	COX-2	The aorta	STZ-induced diabetes rats	Improve vascular dysfunction [15]
Dapagliflozin	PKG/Kv channels	The rabbit aorta	Normal	Improve vascular dysfunction [16]
Dapagliflozin; empagliflozin	TNF-α/ROS/NO	Human coronary arterial endothelial cells	TNF-α stimulation	Improve vascular dysfunction [17]
empagliflozin	L-arginine/NO	Coronary arteries	ob/ob^−/− mice	Improve vascular dysfunction [18]
Empagliflozin; canagliflozin	NHE1	Coronary arteries	Normal mice	Improve vascular dysfunction [19]
Empagliflozin	AMP/ATP/AMPK/Drp1	Heart	STZ-induced diabetic mice	Increase the number of CD31 + microvessels [20]
Empagliflozin	AGEs/RAGE/PKC-ζ/MAPK	Kidney	STZ-induced diabetic rats	Inhibit fibrosis [21]
Empagliflozin	TGF-β/SMAD	Heart	Genetic type 2 diabetes mouse model	Inhibit fibrosis [22]
Dapagliflozin	STAT3	Heart	Myocardial infarction in rats	Inhibit fibrosis [23]
Empagliflozin	NO/sGC-cGMP/PKG pathway [24, 25]	Heart	Human and murine HFpEF myocardium	Reduce cardiomyocyte stiffness [26]
Empagliflozin	Nrf2/ARE pathway	Heart	Genetic type 2 diabetes mouse model	Inhibit oxidative stress [22]
Canagliflozin	AMPK/Akt/eNOS	Heart	ISO-induced oxidative stress in rats	Inhibit oxidative stress [27]
Canagliflozin	iNOS, NOX4	Heart	ISO-induced oxidative stress in rats	Inhibit oxidative stress [27]
Empagliflozin	Sirt1/Nrf2; Sirt1/Foxo1 [28, 29]	Liver and kidney	Otsuka long-evans tokushima fatty rats, rats with induced insulin resistance	Inhibit oxidative stress [30, 31]
Dapagliflozin, Empagliflozin	ERK/Bax; STAT3/Bcl-2; AMPK/TNF-α; Caspase -3	Heart	LPS-induced inflammation in mouse atrial myocytes; cardiorenal syndrome in rats; rats with cardiac I/R injury	Inhibit apoptosis [12, 32, 33]
Dapagliflozin	AMPK/NLRP3/ASC/caspase-1 pathway	Heart	BTBR ob/ob mice	Inhibit pyroptosis [34]
Empagliflozin	CD36/AMPK/Ulk1/Beclin1	Heart	ZDF rats	Promote autophagy [4, 35]
Empagliflozin	NHE1 and NHE1-related genes	Heart	db/db mice with myocardial infarction	Inhibit autophagy [36]
Empagliflozin	Beclin1	Heart	Myocardial infarction with acute hyperglycaemia in mice	Inhibit autophagy [37]
Dapagliflozin	SIRT1/PERK/eIF2α/ATF4/CHOP	Heart	Heart pressure-overload in mice; myocardial I/R injury in mice	Improve ER stress [38, 39]
Dapagliflozin	Abundance of Akkermansia muciniphila	Gut	Diabetic mice homozygous for a point mutation in the leptin receptor gene	Improve glucose tolerance and atherosclerosis [40]
Luseogliflozin, empagliflozin	The abundance of SCFA-producing bacteria	Gut	db/db mice	Improve glucose tolerance and atherosclerosis [41, 42]

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