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Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects

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Abstract

Diabetes is a global epidemic and a leading cause of death with more than 422 million patients worldwide out of whom around 392 million alone suffer from type 2 diabetes (T2D). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are novel and effective drugs in managing glycemia of T2D patients. These inhibitors gained recent clinical and basic research attention due to their clinically observed cardiovascular protective effects. Although interest in the study of various SGLT isoforms and the effect of their inhibition on cardiovascular function extends over the past 20 years, an explanation of the effects observed clinically based on available experimental data is not forthcoming. The remarkable reduction in cardiovascular (CV) mortality (38%), major CV events (14%), hospitalization for heart failure (35%), and death from any cause (32%) observed over a period of 2.6 years in patients with T2D and high CV risk in the EMPA-REG OUTCOME trial involving the SGLT2 inhibitor empagliflozin (Empa) have raised the possibility that potential novel, more specific mechanisms of SGLT2 inhibition synergize with the known modest systemic improvements, such as glycemic, body weight, diuresis, and blood pressure control. Multiple studies investigated the direct impact of SGLT2i on the cardiovascular system with limited findings and the pathophysiological role of SGLTs in the heart. The direct impact of SGLT2i on cardiac homeostasis remains controversial, especially that SGLT1 isoform is the only form expressed in the capillaries and myocardium of human and rodent hearts. The direct impact of SGLT2i on the cardiovascular system along with potential lines of future research is summarized in this review.

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Abbreviations

SGLT:

sodium/glucose cotransporter

WHO:

World Health Organization

Ca2+ :

calcium

T2D:

type 2 diabetes

CV:

cardiovascular

Empa:

empagliflozin

MI:

myocardial infarction

CVD:

cardiovascular disease

NHE:

sodium hydrogen exchanger

NCX:

sodium calcium exchanger

SERCA2a:

sarcoplasmic-reticulum calcium ATPase 2a

Dapa:

dapagliflozin

STZ:

streptozotocin

[Na+]c:

cytoplasmic Na+ concentration

[Ca2+]c:

cytoplasmic Ca2+ concentration

ob/ob:

leptin-deficient homozygous T2D mouse model

LV:

left ventricle

db/db:

C57BLKS/J-Leprdb/Leprdb T2D mouse model

SGK1:

serum/glucocorticoid regulated kinase 1

FFAs:

free fatty acids

TG:

triglyceride

PDH:

pyruvate dehydrogenase

PPARα:

peroxisome proliferator-activated receptor alpha

PDK4:

pyruvate dehydrogenase lipoamide kinase isozyme 4

AGEs:

advanced glycation end products

PPP:

pentose phosphate pathway

HBP:

hexosamine biosynthesis pathway

ROS:

reactive oxygen species

OxPhos:

oxidative phosphorylation

ATP:

adenosine triphosphate

SKO:

lipodystrophic Bscl2−/− (seipin knockout [SKO]) T2D mouse model

HFHS:

high-fat-high-sugar

EFV:

epicardial fat volume

DKA:

diabetic ketoacidosis

RONS:

reactive oxygen and nitrogen species

NLRP:

nucleotide binding domain leucine rich repeat containing protein

IL:

interleukin

NO:

nitric oxide

Phlor:

phlorizin

Cana:

canagliflozin

hsCRP:

high sensitivity C-reactive protein

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Acknowledgements

The authors are grateful for the generous support of the Department of Pharmacology and Toxicology of the University of Mississippi Medical Center and the Department of Pharmacology and Toxicology at the American University of Beirut.

Funding Source

This work was supported by grants from the American University of Beirut (Seed grant #100410, MPP grant #320145) to FAZ.

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  1. Abdullah Kaplan and Emna Abidi contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, American University of Beirut & Medical Center, Riad El-Solh, Beirut, 1107 2020, Lebanon

    Abdullah Kaplan, Emna Abidi, Ahmed El-Yazbi, Ali Eid & Fouad A. Zouein

  2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

    Ahmed El-Yazbi

  3. Department of Biological and Environmental Sciences, Qatar University, Doha, Qatar

    Ali Eid

  4. Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, USA

    George W. Booz

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  1. Abdullah Kaplan
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Kaplan, A., Abidi, E., El-Yazbi, A. et al. Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects. Heart Fail Rev 23, 419–437 (2018). https://doi.org/10.1007/s10741-017-9665-9

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