Cardiovascular protection by SGLT2 inhibitors – Do anti-inflammatory mechanisms play a role?

Elrakaybi, Asmaa; Laubner, Katharina; Zhou, Qian; Hug, Martin; Seufert, Jochen

doi:10.1016/j.molmet.2022.101549

Cited by 43 publications

(28 citation statements)

References 286 publications

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“… 90 Finally, since the principal mechanism by which intracellular ferritin declines is related to ferritinophagy, it is noteworthy that SIRT1 can promote ferritinophagy either by a direct effect to promote autophagic flux 59 , 60 or through stimulation of HIF‐2α‐mediated increases in the expression of NCOA4, 91 thus promoting ferritinophagy. Additionally, the well‐established action of SGLT2 inhibitors to mute inflammation in the heart and bone marrow 92 , 93 , 94 (also the result of enhanced SIRT1 signalling 93 , 94 , 95 ) might contribute to the observed decline in both hepcidin and ferritin. Finally, increased erythropoietin activity upregulates TfR1 and reduces transferrin saturation, ferritin and hepcidin.…”

Section: Effect Of Sodium–glucose Cotransporter 2 Inhibitors On Iron ...mentioning

confidence: 99%

How can sodium–glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron‐deficient? Implications for understanding iron homeostasis in heart failure

Packer

2022

European J of Heart Fail

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Many patients with heart failure have an iron‐deficient state, which can limit erythropoiesis in erythroid precursors and ATP production in cardiomyocytes. Yet, treatment with sodium–glucose cotransporter 2 (SGLT2) inhibitors produces consistent increases in haemoglobin and haematocrit, even in patients who are iron‐deficient before treatment, and this effect remains unattenuated throughout treatment even though SGLT2 inhibitors further aggravate biomarkers of iron deficiency. Heart failure is often accompanied by systemic inflammation, which activates hepcidin, thus impairing the duodenal absorption of iron and the release of iron from macrophages and hepatocytes, leading to a decline in circulating iron. Inflammation and oxidative stress also promote the synthesis of ferritin and suppress ferritinophagy, thus impairing the release of intracellular iron stores and leading to the depletion of bioreactive cytosolic Fe2+. By alleviating inflammation and oxidative stress, SGLT2 inhibitors down‐regulate hepcidin, upregulate transferrin receptor protein 1 and reduce ferritin; the net result is to increase the levels of cytosolic Fe2+ available to mitochondria, thus enabling the synthesis of heme (in erythroid precursors) and ATP (in cardiomyocytes). The finding that SGLT2 inhibitors can induce erythrocytosis without iron supplementation suggests that the abnormalities in iron diagnostic tests in patients with mild‐to‐moderate heart failure are likely to be functional, rather than absolute, that is, they are related to inflammation‐mediated trapping of iron by hepcidin and ferritin, which is reversed by treatment with SGLT2 inhibitors. An increase in bioreactive cytosolic Fe2+ is also likely to augment mitochondrial production of ATP in cardiomyocytes, thus retarding the progression of heart failure. These effects on iron metabolism are consistent with (i) proteomics analyses of placebo‐controlled trials, which have shown that biomarkers of iron homeostasis represent the most consistent effect of SGLT2 inhibitors; and (ii) statistical mediation analyses, which have reported striking parallelism of the effect of SGLT2 inhibitors to promote erythrocytosis and reduce heart failure events.

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Section: Effect Of Sodium–glucose Cotransporter 2 Inhibitors On Iron ...mentioning

confidence: 99%

How can sodium–glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron‐deficient? Implications for understanding iron homeostasis in heart failure

Packer

2022

European J of Heart Fail

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“…A central mechanism for the urate-lowering effect of SGLT2i is thought to be through increased glycosuria, which in turn competes with soluble urate for GLUT9-mediated reabsorption in the proximal tubule, enhancing urinary urate excretion. Furthermore, by enhancing the SIRT-1 signaling pathway, SGLT2i may reduce oxidative stress and downregulate xanthine oxidase, thereby lowering serum urate extrarenally . Moreover, the known effects of SGLT2i of improving kidney function, heart failure, body weight, blood pressure reduction, and insulin resistance may also contribute to serum urate reductions, leading to lower risk of gout .…”

Section: Discussionmentioning

confidence: 99%

Sodium-Glucose Cotransporter-2 Inhibitors vs Sulfonylureas for Gout Prevention Among Patients With Type 2 Diabetes Receiving Metformin

McCormick,

Yokose,

et al. 2024

JAMA Intern Med

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ImportanceSodium-glucose cotransporter type 2 inhibitors (SGLT2i) are a revolutionary treatment for type 2 diabetes (T2D) with cardiovascular, kidney, and serum urate-lowering benefits.ObjectiveTo compare risk of incident gout and rate of recurrent flares between patients with T2D initiating SGLT2i vs sulfonylurea, most common second-line glucose-lowering therapy, when added to metformin monotherapy.Design, Setting, and ParticipantsThis sequential, propensity score-matched, new-user comparative effectiveness study using target trial emulation framework included adults with T2D receiving metformin monotherapy in a Canadian general population database from January 1, 2014, to June 30, 2022.ExposuresInitiation of SGLT2i vs sulfonylurea.Main Outcomes and MeasuresThe primary outcome was incident gout diagnosis, ascertained by emergency department (ED), hospital, outpatient, and medication dispensing records. Secondary outcomes were gout-primary hospitalizations and ED visits and major adverse cardiovascular events (MACE), as well as recurrent flare rates among prevalent gout patients. Heart failure (HF) hospitalization was assessed as positive control outcome and osteoarthritis encounters as negative control. For target trial emulations, we used Cox proportional hazards and Poisson regressions with 1:1 propensity score matching (primary analysis) and overlap weighting (sensitivity analysis). The analysis was conducted from September to December, 2023.ResultsAmong 34 604 propensity score matched adults with T2D initiating SGLT2i or sulfonylurea (20 816 [60%] male, mean [SD] age, 60 [12.4] years), incidence of gout was lower among SGLT2i initiators (4.27 events per 1000 person-years) than sulfonylurea initiators (6.91 events per 1000 person-years), with a hazard ratio (HR) of 0.62 (95% CI, 0.48-0.80) and a rate difference (RD) of −2.64 (95% CI, −3.99 to −1.29) per 1000 person-years. Associations persisted regardless of sex, age, or baseline diuretic use. SGLT2i use was also associated with fewer recurrent flares among gout patients (rate ratio, 0.67; 95% CI, 0.55-0.82; and RD, −20.9; 95% CI, −31.9 to −10.0 per 1000 person-years). HR and RD for MACE associated with SGLT2i use were 0.87 (95% CI, 0.77-0.98) and −3.58 (95% CI, −6.19 to −0.96) per 1000 person-years. For control outcomes, SGLT2i users had lower risk of HF (HR, 0.53; 95% CI, 0.38-0.76), as expected, with no difference in osteoarthritis (HR, 1.11; 95% CI, 0.94-1.34). Results were similar when applying propensity score overlap weighting.ConclusionsIn this population-based cohort study, the gout and cardiovascular benefits associated with SGLT2i in these target trial emulations may guide selection of glucose-lowering therapy in patients with T2D, at risk for or already with gout.

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“…The cardiovascular benefits of SGLT2 inhibitors in heart failure, thus, could also be achieved in glucose-independent manner by acting as an antioxidant restoring oxidant-antioxidant balance through several mechanisms including inhibition of eNOS uncoupling, downregulation of NADPH oxidase expression, and attenuation of overexpressed superoxide dismutase 25 . Additionally, SGLT2 inhibitors have been shown to reduce inflammation and oxidative stress, both of which can contribute to the development and cardiovascular disease 26 . Enavogliflozin (DWP16001) is one of the selective SGLT2 inhibitors under development by Daewoong Pharmaceutical Co., Ltd (Seoul, Korea) which has recently approved by MFDS of Korea (Ministry of Food and Drug Safety).…”

Section: Discussionmentioning

confidence: 99%

SGLT2 inhibition ameliorates nano plastics-induced premature endothelial senescence and dysfunction

Dhakal

Shiwakoti

Park

et al. 2023

Sci Rep

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Nano plastics (NPs) have been a significant threat to human health and are known to cause premature endothelial senescence. Endothelial senescence is considered one of the primary risk factors contributing to numerous cardiovascular disorders. Recent studies have suggested that inhibition of sodium glucose co-transporter (SGLT2) ameliorates endothelial senescence and dysfunction. Therefore, our study intends to explore the role of SGLT2 in NPs-induced endothelial senescence and dysfunction. Porcine coronary artery and its endothelial cells were treated with NPs in the presence or absence of Enavogliflozin (ENA), a SGLT2 inhibitor and then SGLTs expression, senescence markers and vascular function were evaluated. NPs significantly up-regulated SGLT2 and ENA significantly decreased NPs-induced senescence-associated-β‐gal activity, cell‐cycle arrest, and senescence markers p53 and p21 suggesting that inhibition of SGLT2 prevents NPs-induced endothelial senescence. In addition, ENA decreased the formation of reactive oxygen species with the downregulation of Nox2, and p22phox. Furthermore, SGLT2 inhibition also up regulated the endothelial nitric oxide synthase expression along with improving vascular function. In conclusion, premature endothelial senescence by NPs is, at least in part, associated with SGLT2 and it could be a potential therapeutic target for preventing and/or treating environmental pollutants-induced cardiovascular disorders mediated by endothelial senescence and dysfunction.

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Cardiovascular protection by SGLT2 inhibitors – Do anti-inflammatory mechanisms play a role?

Cited by 43 publications

References 286 publications

How can sodium–glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron‐deficient? Implications for understanding iron homeostasis in heart failure

How can sodium–glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron‐deficient? Implications for understanding iron homeostasis in heart failure

Sodium-Glucose Cotransporter-2 Inhibitors vs Sulfonylureas for Gout Prevention Among Patients With Type 2 Diabetes Receiving Metformin

SGLT2 inhibition ameliorates nano plastics-induced premature endothelial senescence and dysfunction

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