Cardiorenal protection of SGLT2 inhibitors—Perspectives from metabolic reprogramming

Gao, Yan; Feng, Songtao; Wen, Yi; Tang, Tao-Tao; Wang, Bin; Liu, Bi-Cheng

doi:10.1016/j.ebiom.2022.104215

Cited by 46 publications

(33 citation statements)

References 121 publications

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“…In addition, reduced expression of inflammatory markers such as IL-6, TNF-α and adhesion molecules by SGLT2 inhibition in a glucose concentration-independent fashion has been shown mainly in experimental studies [ 44 , 45 ], though the association between BAIBA and activation of NLRP3 inflammasome, a known off-target of an SGLT2i, has not been investigated. Third, there is a hypothesis that elevated ketone concentration is attributable to SGLT2i-mediated protection from HF, though there are some debates [ 5 , 14 ]. Ketones, which are known to be upregulated by SGLT2 inhibition in plasma, have been shown to provide ATP more efficiently than fatty acids and serve as an activator of protective molecular signaling [ 5 , 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…Third, there is a hypothesis that elevated ketone concentration is attributable to SGLT2i-mediated protection from HF, though there are some debates [ 5 , 14 ]. Ketones, which are known to be upregulated by SGLT2 inhibition in plasma, have been shown to provide ATP more efficiently than fatty acids and serve as an activator of protective molecular signaling [ 5 , 14 ]. Increased production of free fatty acid by lipolysis and enhanced glucagon/insulin ratio are a possible primary mechanism of ketone production by SGLT2 inhibition [ 5 , 14 , 46 ], but the mechanisms by which SGLT2 inhibition upregulates ketone production remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…Ketones, which are known to be upregulated by SGLT2 inhibition in plasma, have been shown to provide ATP more efficiently than fatty acids and serve as an activator of protective molecular signaling [ 5 , 14 ]. Increased production of free fatty acid by lipolysis and enhanced glucagon/insulin ratio are a possible primary mechanism of ketone production by SGLT2 inhibition [ 5 , 14 , 46 ], but the mechanisms by which SGLT2 inhibition upregulates ketone production remain poorly understood. BAIBA-induced enhancement of β-oxidation in hepatocytes, leading to ketone production, is an attractive candidate for the mechanism of SGLT2i-induced increase in circulating ketones.…”

Section: Discussionmentioning

confidence: 99%

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Elevated circulating level of β-aminoisobutyric acid (BAIBA) in heart failure patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitors

Katano

Yano

Kouzu

et al. 2022

Cardiovasc Diabetol

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Aims The mechanism by which a sodium-glucose cotransporter inhibitor (SGLT2i) induces favorable effects on diabetes and cardiovascular diseases including heart failure (HF) remains poorly understood. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiles are modulated by SGLT2i use in HF patients with type 2 diabetes mellitus (T2DM). Methods We retrospectively examined 81 HF patients with T2DM (68 ± 11 years old; 78% male). Plasma amino acid concentrations in a fasting state after stabilization of HF were determined using ultraperformance liquid chromatography. To minimize potential selection bias in the retrospective analyses, the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an inverse probability of treatment weighting (IPTW)-adjusted analysis. Results Of amino acids measurable in the present assay, plasma β-aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule also known as 3-aminoisobutyric acid or 3-amino-2-methyproponic acid, was detected in 77% of all patients and the proportion of patients in whom plasma BAIBA was detected was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (93% vs. 67%, p = 0.01). Analyses in patients in whom plasma BAIBA was detected showed that plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (6.76 ± 4.72 vs. 4.56 ± 2.93 nmol/ml, p = 0.03). In multivariate logistic regression analyses that were adjusted for age and sex, SGLT2i use was independently associated with BAIBA detection. The independent association between BAIBA and SGLT2i use remained after inclusion of body mass index, HF with reduced ejection fraction, ischemic etiology, renal function, NT-proBNP, albumin, hemoglobin, and HbA1c into the Cox proportional hazards model. When the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an IPTW-adjusted analysis, least squares mean of plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i. Conclusion SGLT2i use is closely associated with increased circulating BAIBA concentration in HF patients with T2DM.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Elevated circulating level of β-aminoisobutyric acid (BAIBA) in heart failure patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitors

Katano

Yano

Kouzu

et al. 2022

Cardiovasc Diabetol

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show abstract

“…53 SGLT2 inhibitors are proposed to mitigate heart and kidney risk through multiple mechanisms (Figure 1). [54][55][56] When used clinically, SGLT2 inhibitors are associated with reductions in glycaemia, weight and blood pressure, and with ketogenesis and erythrocytosis. 54 The glycaemic effects of SGLT2 inhibition (the indication for which this class of medications was developed) do not fully account for the organ benefits of SGLT2 inhibitors observed in outcome trials, especially when considering the benefits in participants without diabetes that have been observed in several HF and kidney outcome trials.…”

Section: Proposed Mechanisms For Cardiovascular and Kidney Benefit Wi...mentioning

confidence: 99%

“…54 In addition to their effects on tubulo-glomerular feedback, SGLT2 inhibitors also likely convey additional anti-inflammatory, anti-fibrotic, energetic and cardiac remodelling benefits that protect the heart and kidney (Figure 1). [54][55][56] By inducing a biologic state that mimics starvation, SGLT2 4). 16,18,64,65 Based on observed HF benefits in patients with and without T2D, the 2022 heart failure guidelines from the American Heart Association/ American College of Cardiology/Heart Failure Society of America recommend SGLT2 inhibitors within their treatment algorithm to improve HF outcomes.…”

Section: Proposed Mechanisms For Cardiovascular and Kidney Benefit Wi...mentioning

confidence: 99%

Clinical Evidence and Proposed Mechanisms for Cardiovascular and Kidney Benefits from Sodium–Glucose Co-transporter-2 Inhibitors

Neumiller¹,

Lienhard²,

Alicic³

et al. 2022

European Endocrinology

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The number of people living with type 2 diabetes (T2D) and its complications worldwide is increasing at an alarming rate. Fortunately, our understanding of the benefits of glucose-lowering agents from the sodium–glucose co-transporter-2 (SGLT2) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist classes on cardiovascular and kidney outcomes is advancing; this means we now have new options to mitigate the risks of these complications in patients with T2D. The SGLT2 inhibitors have consistently demonstrated benefits on atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD) and heart failure (HF) events in dedicated outcome trials. Large guidelines groups now recommend SGLT2 inhibitors as a standard of care in patients with T2D and comorbid ASCVD, CKD and/or HF. Evolving evidence additionally indicates kidney and HF benefits of SGLT2 inhibitors in populations without diabetes. These agents likely provide heart and kidney benefits through multiple mechanisms, as their impact on heart and kidney outcomes cannot be fully explained by their direct metabolic effects. On-going work to elucidate the beneficial mechanisms at play with SGLT2 inhibitors will help further optimize these life-saving therapies in patients with and without T2D.

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Hyperglycemia and Diabetes in the Posttransplant Patient

Dowlatshahi,

Zahid,

Sadhu

2023

Contemporary Endocrinology

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Cardiorenal protection of SGLT2 inhibitors—Perspectives from metabolic reprogramming

Cited by 46 publications

References 121 publications

Elevated circulating level of β-aminoisobutyric acid (BAIBA) in heart failure patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitors

Elevated circulating level of β-aminoisobutyric acid (BAIBA) in heart failure patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitors

Clinical Evidence and Proposed Mechanisms for Cardiovascular and Kidney Benefits from Sodium–Glucose Co-transporter-2 Inhibitors

Hyperglycemia and Diabetes in the Posttransplant Patient

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