SGLT2 inhibitors: a focus on cardiac benefits and potential mechanisms

Nikolić, Milutin; Živković, Vladimir; Jovic, Jovana Joksimovic; Sretenovic, Jasmina; Davidović, Goran; Simović, Stefan; Djokovic, Danijela; Muric, Nemanja; Bolevich, Sergey; Jakovljević, Vladimir

doi:10.1007/s10741-021-10079-9

Cited by 25 publications

(21 citation statements)

References 145 publications

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“…However, the exact cardio-protective mechanism of action is still unclear—especially since SGLT2 receptors are not expressed in the heart [ 22 , 23 ]. Several favorable effects of SGLT2 inhibitors such as increased diuresis [ 24 ], decreased arterial stiffness [ 25 ], weight and blood pressure reduction [ 1 , 26 ], and other cardiac benefits [ 27 ] contribute to positive outcomes in heart failure. The cardioprotective effects were also attributed to the modification of the cardiac metabolome and anti-oxidants [ 13 ], increased energy production from glucose, ketone bodies and fatty acid oxidation [ 10 , 28 ], anti-inflammation [ 29 ], and improved myocardial oxidative phosphorylation [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Low-Dose Empagliflozin Improves Systolic Heart Function after Myocardial Infarction in Rats: Regulation of MMP9, NHE1, and SERCA2a

Goerg

Sommerfeld

Greiner

et al. 2021

IJMS

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The effects of the selective sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin in low dose on cardiac function were investigated in normoglycemic rats. Cardiac parameters were measured by intracardiac catheterization 30 min after intravenous application of empagliflozin to healthy animals. Empagliflozin increased the ventricular systolic pressure, mean pressure, and the max dP/dt (p < 0.05). Similarly, treatment with empagliflozin (1 mg/kg, p.o.) for one week increased the cardiac output, stroke volume, and fractional shortening (p < 0.05). Myocardial infarction (MI) was induced by ligation of the left coronary artery. On day 7 post MI, empagliflozin (1 mg/kg, p.o.) improved the systolic heart function as shown by the global longitudinal strain (−21.0 ± 1.1% vs. −16.6 ± 0.7% in vehicle; p < 0.05). In peri-infarct tissues, empagliflozin decreased the protein expression of matrix metalloproteinase 9 (MMP9) and favorably regulated the cardiac transporters sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) and sodium hydrogen exchanger 1 (NHE1). In H9c2 cardiac cells, empagliflozin decreased the MMP2,9 activity and prevented apoptosis. Empagliflozin did not alter the arterial stiffness, blood pressure, markers of fibrosis, and necroptosis. Altogether, short-term treatment with low-dose empagliflozin increased the cardiac contractility in normoglycemic rats and improved the systolic heart function in the early phase after MI. These effects are attributed to a down-regulation of MMP9 and NHE1, and an up-regulation of SERCA2a. This study is of clinical importance because it suggests that a low-dose treatment option with empagliflozin may improve cardiovascular outcomes post-MI. Down-regulation of MMPs could be relevant to many remodeling processes including cancer disease.

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Section: Introductionmentioning

confidence: 99%

Low-Dose Empagliflozin Improves Systolic Heart Function after Myocardial Infarction in Rats: Regulation of MMP9, NHE1, and SERCA2a

Goerg

Sommerfeld

Greiner

et al. 2021

IJMS

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“…This latter suggests that an early glycemia normalization can arrest hyperglycemiainduced epigenetic processes associated with enhanced oxidative stress and glycation of cellular proteins and lipids. 71,72 In parallel, an increasing number of clinical trials is evaluating the putative beneficial repurposing of metformin, statins, SGLT2i, and PUFAs in patients with HFpEF and/or HFrEF; 19,[62][63][64]69,[73][74][75] however, despite experimental evidence, none of these trials evaluated their potential epigenetic effects involved in improving the cardiac function. This gap should be overcome to improve personalized therapy of patients with HF.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Therapies for Heart Failure: Current Insights and Future Potential

Napoli

Bontempo

Palmieri

et al. 2021

VHRM

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Despite the current reductionist approach providing an optimal indication for diagnosis and treatment of patients with heart failure with reduced ejection fraction (HFrEF), there are no standard pharmacological therapies for heart failure with preserved ejection fraction (HFpEF). Although in its infancy in cardiovascular diseases, the epigenetic-based therapy ("epidrugs") is capturing the interest of physician community. In fact, an increasing number of controlled clinical trials is evaluating the putative beneficial effects of: 1) direct epigenetic-oriented drugs, eg, apabetalone, and 2) repurposed drugs with a possible indirect epigenetic interference, eg, metformin, statins, sodium glucose transporter inhibitors 2 (SGLT2i), and omega 3 polyunsaturated fatty acids (PUFAs) in both HFrEF and HFpEF, separately. Apabetalone is the first and unique direct epidrug tested in cardiovascular patients to date, and the BETonMACE trial has reported a reduction in first HF hospitalization (any EF value) and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome, suggesting a possible role in secondary prevention. Patients with HFpEF seem to benefit from supplementation to the standard therapy with statins, metformin, and SGLT2i owing to their ability in reducing mortality. In contrast, the vasodilator hydralazine, with or without isosorbide dinitrate, did not provide beneficial effects. In HFrEF, metformin and SGLT2i could reduce the risk of incident HF and mortality in affected patients whereas clinical trials based on statins provided mixed results. Furthermore, PUFAs diet supplementation was significantly associated with reduced cardiovascular risk in both HFpEF and HFrEF. Future large trials will reveal whether direct and indirect epitherapy will remain a work in progress or become a useful way to customize the therapy in the real-world management of HFpEF and HFrEF. Our goal is to discuss the recent advancement in the epitherapy as a possible way to improve personalized therapy of HF.

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“…Other explanations relate to reduction of uric acid levels, and of epicardial adipose tissue with beneficial paracrine regulation of adipokines and reduced serum leptin levels [24]. Improved cardiac energy by increased glucagon utilization and shifting metabolism from fatty-acid oxidation to glucose has also been considered [27]. Another possibility is a direct cardiac effect through inhibition of sodium-hydrogen exchange which, in turn, may lead to reduction in cardiac remodeling [26].…”

Section: Sodium-glucose Co-transporters 2 Inhibitors (Sglt2i)mentioning

confidence: 99%

Looking for a Tailored Therapy for Heart Failure: Are We Capable of Treating the Patient Instead of the Disease?

Fucili

Cimaglia

Severi

et al. 2021

JCM

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After almost a decade of stagnation in clinical research for HF treatment, five large randomized trials recently published have supported the use of four new classes of drugs, namely: angiotensin receptor/neprilysin inhibitor, sodium–glucose co-transporters 2 inhibitors, soluble guanylate cyclase modulators, and myosin activators. Each treatment has proved to be beneficial for both long-term outcomes and quality of life. Beside their clinical relevance, all these novel treatments have a different mechanism of action beyond the usual neuro-hormonal blockage. These different pathways, together with the unquestionable clinical evidence, advocate a re-thinking of HF treatment and of the appropriate drug to integrate with the existing standard therapy, according to different characteristics of HFrEF patients. This study aimed to offer a synthetic overview of the mechanisms of action of the new drugs and to propose a more personalized approach, considering patients’ characteristics and safety profiles. To this end, we have identified seven profiles for patients with chronic heart failure with reduced ejection fraction and two for pre-discharge patients.

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SGLT2 inhibitors: a focus on cardiac benefits and potential mechanisms

Cited by 25 publications

References 145 publications

Low-Dose Empagliflozin Improves Systolic Heart Function after Myocardial Infarction in Rats: Regulation of MMP9, NHE1, and SERCA2a

Low-Dose Empagliflozin Improves Systolic Heart Function after Myocardial Infarction in Rats: Regulation of MMP9, NHE1, and SERCA2a

Epigenetic Therapies for Heart Failure: Current Insights and Future Potential

Looking for a Tailored Therapy for Heart Failure: Are We Capable of Treating the Patient Instead of the Disease?

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