Mechanisms of Sodium–Glucose Cotransporter 2 Inhibition: Insights From Large-Scale Proteomics

Ferrannini, Ele; Murthy, Ashwin; Lee, Yong-Ho; Muscelli, Elza; Weiss, Sophie; Ostroff, Rachel; Sattar, Naveed; Williams, Stephen; Gänz, Peter

doi:10.2337/dc20-0456

Cited by 41 publications

(37 citation statements)

References 54 publications

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“…These benefits have long moved beyond its role as antidiabetic drugs, which bring SGLT2is to the forefront. Recent studies have also found that SGLT2is can modulate iron metabolism and maintain body iron homeostasis as well as cardiac iron homeostasis (31,32). Here, the role of ferroptosis in protecting myocardial function by SGLT2is has attracted more and more attention.…”

Section: Discussionmentioning

confidence: 99%

Canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy

Shi

Xiong

et al. 2022

Front. Endocrinol.

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Canagliflozin (Cana), an anti-diabetes drug belongs to sodium-glucose cotransporter 2 inhibitor, is gaining interest because of its extra cardiovascular benefits. Ferroptosis is a new mode of cell death, which can promote the occurrence of diabetic cardiomyopathy (DCM). Whether Cana can alleviate DCM by inhibiting ferroptosis is the focus of this study. Here, we induced DCM models in diabetic C57BL6 mice and treated with Cana. Meanwhile, in order to exclude its hypoglycemic effect, the high glucose model in H9C2 cells were established. In the in vivo study, we observed that Cana could effectively alleviate the damage of cardiac function in DCM mice, including the increasing of lactate dehydrogenase (LDH) and cardiac troponin I (cTnI), the alleviating of myocardial fiber breakage, inflammation, collagen fiber deposition and mitochondrial structural disorder. We evaluated reactive oxygen species (ROS) levels by DCFH-DA and BODIPY 581/591 C11, in vitro Cana reduced ROS and lipid ROS in H9C2 cells induced by high glucose. Meanwhile, JC-1 fluorochrome assay showed that the decreased mitochondrial membrane potential (MMP) was increased by Cana. Furthermore, the inhibitory effects of Cana on myocardial oxidative stress and ferroptosis were verified in vivo and in vitro by protein carbonyl (PCO), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH). As a key inducer of ferroptosis, the deposition of total iron and Fe2+ can be inhibited by Cana both in vivo and in vitro. In addition, western blot results indicated that the expression of ferritin heavy-chain (FTN-H) was down-regulated, and cystine-glutamate antiporter (xCT) was up-regulated by Cana in DCM mice and cells, suggesting that Cana inhibit ferroptosis by balancing cardiac iron homeostasis and promoting the system Xc-/GSH/GPX4 axis in DCM. These findings underscore the fact that ferroptosis plays an important role in the development and progression of DCM and targeting ferroptosis may be a novel strategy for prevention and treatment. In conclusion, Cana may exert some of its cardiovascular benefits by attenuating ferroptosis.

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Section: Discussionmentioning

confidence: 99%

Canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy

Shi

Xiong

et al. 2022

Front. Endocrinol.

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“…Of the metabolic benefits, SGLT2 inhibitors demonstrated a reduction of blood glucose, body weight, and as well as an improved insulin resistance in HFrEF patients [ 22 – 24 ]. A recent proteomic study revealed an increase in plasma GDF-15 by empagliflozin in patients with diabetes or impaired glucose tolerance [ 25 ], however, it is unknown whether the SGL2Ti mediated improvement of HFrEF is accompanied by a change in plasma of GDF-15 levels.…”

Section: Introductionmentioning

confidence: 99%

The effect of empagliflozin on growth differentiation factor 15 in patients with heart failure: a randomized controlled trial (Empire HF Biomarker)

Omar

Jensen

Kistorp

et al. 2022

Cardiovasc Diabetol

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Background Plasma growth differentiation factor-15 (GDF-15) biomarker levels increase in response to inflammation and tissue injury, and increased levels of GDF-15 are associated with increased risk of mortality in patients with heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter-2 (SGLT2) inhibitors, which improve outcome in HFrEF, have been shown to increase plasma GDF-15 in diabetic patients. We aimed to investigate the effect of empagliflozin on GDF-15 in HFrEF patients. Methods This Empire HF Biomarker substudy was from the multicentre, randomized, double-blind, placebo-controlled Empire HF trial that included 190 patients from June 29, 2017, to September 10, 2019. Stable ambulatory HFrEF patients with ejection fraction of ≤ 40% were randomly assigned (1:1) to empagliflozin 10 mg once daily, or matching placebo for 12 weeks. Changes from baseline to 12 weeks in plasma levels of GDF-15, high-sensitive C-reactive protein (hsCRP), and high-sensitive troponin T (hsTNT) were assessed. Results A total of 187 patients who were included in this study, mean age was 64 ± 11 years; 85% male, 12% with type 2 diabetes, mean ejection fraction 29 ± 8, with no differences between the groups. Baseline median plasma GDF-15 was 1189 (918–1720) pg/mL with empagliflozin, and 1299 (952–1823) pg/mL for placebo. Empagliflozin increased plasma GDF-15 compared to placebo (adjusted between-groups treatment effect; ratio of change (1·09 [95% confidence interval (CI), 1.03–1.15]: p = 0.0040). The increase in plasma GDF15 was inversely associated with a decrease in left ventricular end-systolic (R = – 0.23, p = 0.031), and end-diastolic volume (R = – 0.29, p = 0.0066). There was no change in plasma hsCRP (1.09 [95%CI, 0.86–1.38]: p = 0.48) or plasma hsTNT (1.07 [95%CI, 0.97–1.19]: p = 0.18) compared to placebo. Patients with diabetes and treated with metformin demonstrated no increase in plasma GDF-15 with empagliflozin, p for interaction = 0·01. Conclusion Empagliflozin increased plasma levels of GDF-15 in patients with HFrEF, with no concomitant increase in hsTNT nor hsCRP. Trial registration: The Empire HF trial is registered with ClinicalTrials.gov, NCT03198585.

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“…These results contrast to a prior study of empagliflozin, which reported that empagliflozin increased GDF‐15 levels. 20 However, there are important differences between our trial and the empagliflozin study. First, our study was much larger, involving 3549 patients compared with only 72 in the prior study.…”

Section: Discussionmentioning

confidence: 88%

Association Between Circulating GDF‐15 and Cardio‐Renal Outcomes and Effect of Canagliflozin: Results From the CANVAS Trial

Sen

Neuen

et al. 2021

JAHA

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Background Studies have suggested that sodium glucose co‐transporter 2 inhibitors exert anti‐inflammatory effects. We examined the association of baseline growth differentiation factor‐15 (GDF‐15), a marker of inflammation and cellular injury, with cardiovascular events, hospitalization for heart failure (HF), and kidney outcomes in patients with type 2 diabetes in the CANVAS (Canagliflozin Cardiovascular Assessment Study) and determined the effect of the sodium glucose co‐transporter 2 inhibitor canagliflozin on circulating GDF‐15. Methods and Results The CANVAS trial randomized 4330 people with type 2 diabetes at high cardiovascular risk to canagliflozin or placebo. The association between baseline GDF‐15 and cardiovascular (non‐fatal myocardial infarction, non‐fatal stroke, cardiovascular death), HF, and kidney (40% estimated glomerular filtration rate decline, end‐stage kidney disease, renal death) outcomes was assessed using multivariable adjusted Cox regression models. During median follow‐up of 6.1 years (N=3549 participants with available samples), 555 cardiovascular, 129 HF, and 137 kidney outcomes occurred. Each doubling in baseline GDF‐15 was significantly associated with a higher risk of cardiovascular (hazard ratio [HR], 1.2; 95% CI, 1.0‒1.3), HF (HR, 1.5; 95% CI, 1.2‒2.0) and kidney (HR, 1.5; 95% CI, 1.2‒2.0) outcomes. Baseline GDF‐15 did not modify canagliflozin’s effect on cardiovascular, HF, and kidney outcomes. Canaglifozin treatment modestly lowered GDF‐15 compared with placebo; however, GDF‐15 did not mediate the protective effect of canagliflozin on cardiovascular, HF, or kidney outcomes. Conclusions In patients with type 2 diabetes at high cardiovascular risk, higher GDF‐15 levels were associated with a higher risk of cardiovascular, HF, and kidney outcomes. Canagliflozin modestly lowered GDF‐15, but GDF‐15 reduction did not mediate the protective effect of canagliflozin.

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Mechanisms of Sodium–Glucose Cotransporter 2 Inhibition: Insights From Large-Scale Proteomics

Cited by 41 publications

References 54 publications

Canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy

Canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy

The effect of empagliflozin on growth differentiation factor 15 in patients with heart failure: a randomized controlled trial (Empire HF Biomarker)

Association Between Circulating GDF‐15 and Cardio‐Renal Outcomes and Effect of Canagliflozin: Results From the CANVAS Trial

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