TABLE 3.
Experimental studies to investigate cardioprotective mechanisms of metformin, GLP1-RA, DPP4i, and SGLT2i.
| Treatment | Model | Treatment-induced effects | References |
| Animal models | |||
| Diabetes | |||
| Metformin, 4 months | STZ-induced diabetic mice | Reduced autophagy, apoptosis, and fibrosis Reduced Inflammation, AMPK activation | He et al., 2013; Yang et al., 2019 |
| Metformin, 3 months | Diabetic GK rats | Reduced fibrosis, and arrhythmia | Fu et al., 2018 |
| GLP1-RA – liraglutide, 2 months | STZ-induced, HFD Wistar rats | Improved heart function, reduced fibrosis | Ji et al., 2014 |
| GLP1-RA – liraglutide, 1 week | HFD induced obese, insulin resistant mice | Reduced fibrosis, and inflammation, AMPK activation, activation of RISK pathway (Akt, GSK3β,Erk1/2), increased eNOS expression | Noyan-Ashraf et al., 2013 |
| DPP4i – sitagliptin, 3 months | STZ induced, HFD Wistar rats | Improved cardiac function, reduced fibrosis, lipid accumulation, inflammation, apoptosis, and arrhythmia | Liu et al., 2015 |
| DPP4i – sitagliptin, 5 months | Diabetic GK rats | Improved insulin sensitivity, and diastolic function, increased glucose uptake, AMPK activation | Ramirez et al., 2018 |
| SGLT2i – empagliflozin, 2 weeks | db/db mice | Increased cardiac ATP production and glucose oxidation, improved cardiac function | Verma et al., 2018 |
| SGLT2i – dapagliflozin | BTBR ob/ob mice | Improved cardiac function, reduced inflammation, fibrosis, and apoptosis | Ye et al., 2017 |
| Myocardial infarction/ischemia-reperfusion injury | |||
| Metformin | C57BL/6 mice | Reduced infarct size, improved cardiac output | Calvert et al., 2008 |
| GLP1-RA – liraglutide, 1 week before MI | C57BL/6 mice | Reduced infarct size, improved cardiac output | Noyan-Ashraf et al., 2009 |
| DPP4i – linagliptin, 1 week before MI | C57BL/6J mice, db/db mice | Reduced infarct size, inflammation, fibrosis marker, and apoptosis, improved cardiac output | Birnbaum et al., 2019 |
| SGLT2i – dapagliflozin, 4 weeks before IRI | HFD induced pre-diabetic, obese rats | Reduced apoptosis, ROS, arrhythmia susceptibility, improved heart function | Tanajak et al., 2018 |
| SGLT2i – empagliflozin, 6 weeks before IRI | C57BL/6 mice, HFD | Reduced infarct size, STAT3 activation, independent on Akt, eNOS, Erk1/2, GSK3β | Andreadou et al., 2017 |
| Direct cellular/tissue effects | |||
| Metformin, 1 mM | H9c2 cells, high glucose condition | Reduced autophagy, apoptosis, and fibrosis | He et al., 2013 |
| Metformin, 1 μM | H9c2 cells, high glucose condition | Increased glucose uptake, reduced FA uptake | Johnson et al., 2016 |
| GLP1-RA – liraglutide, 100 nM | H9c2 cells, high glucose condition | Reduced ROS, and apoptosis, improved autophagy | Yu et al., 2018 |
| GLP1-RA – GLP1, 25 nM | Neonatal rat CMs, high fatty-acid medium | Reduced lipid accumulation, and apoptosis | Ying et al., 2015 |
| GLP1-RA – GLP1, 100 nM | Isolated rat CMs, high glucose medium | Reduced ROS, no effect on glucose uptake or glycolysis | Balteau et al., 2014 |
| DPP4i – sitagliptin | H9c2 cells, high glucose conditions | Improved autophagy | Zhou et al., 2018 |
| DPP4i – linagliptin | Human CMs and fibroblasts | Reduced inflammasome activation | Birnbaum et al., 2019 |
| SGLT2i – empagliflozin, 0.5–1 μM | Isolated human trabeculae from T2D patients | Reduction of diastolic stiffness, improvement of diastolic function | Pabel et al., 2018 |
| SGLT2i – empagliflozin, 1 μM | Isolated CMs of HF patients | Increased glucose uptake | Mustroph et al., 2019 |
| SGLT2i – dapagliflozin, 0.5 μM | Mouse cardiac fibroblasts, lipopolysaccharide stimulation | Reduced inflammation markers, AMPK activation | Ye et al., 2017 |
AMPK, adenosine monophosphate-activated protein kinase; CMs, cardiomyocytes; FA, fatty acid; GK, Goto-Kakizaki; HFD, high-fat diet; IRI, ischemia-reperfusion injury; MI, myocardial infarction; ROS, reactive oxygen species; STZ, streptozotocin.