Effects of sodium glucose cotransporter 2 inhibitors on mineral metabolism in type 2 diabetes mellitus

Vinke, Joanna Sophia J; Heerspink, Hiddo J.L.; Borst, Martin H. de

doi:10.1097/mnh.0000000000000505

Cited by 19 publications

(21 citation statements)

References 47 publications

(97 reference statements)

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“…Electrolytes and mineral metabolism. SGLT2is induce small increases in serum concentrations of magnesium 66,67 , potassium 68 and phosphate 69 , yet the potential role of these increases in serum electrolytes levels in cardiovascular protection remains unknown 70 . Nevertheless, the absence of reduction in potassium levels, which contrasts to the common reduction seen with classical diuretics, might be clinically relevant in terms of safety.…”

Section: Box 1 | Sodium-glucose Cotransporter Type 2 Inhibitorsmentioning

confidence: 99%

“…These effects resulted in increased mean levels of serum phosphorus, plasma intact fibroblast growth factor and plasma parathyroid hormone, while decreasing the level of 1,25-dihydroxyvitamin D 49 . Although hyperparathyroidism and vitamin D deficiency could provoke adverse effects on bone health with a higher risk of bone fractures, overall, such deleterious effects have not been convincingly demonstrated with SGLT2is as a class 69 (see later text).…”

Section: Box 1 | Sodium-glucose Cotransporter Type 2 Inhibitorsmentioning

confidence: 99%

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Sodium–glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus

Scheen

2020

Nat Rev Endocrinol

188

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The management of type 2 diabetes mellitus (T2DM) is becoming increasingly complex. Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are the newest antidiabetic agents for T2DM. By targeting the kidney, they have a unique mechanism of action, which results in enhanced glucosuria, osmotic diuresis and natriuresis, thereby improving glucose control with a limited risk of hypoglycaemia and exerting additional positive effects such as weight loss and the lowering of blood pressure. Several outcome studies with canagliflozin, dapagliflozin or empagliflozin reported a statistically significant reduction in major cardiovascular events, hospitalization for heart failure and progression to advanced renal disease in patients with T2DM who have established atherosclerotic cardiovascular disease, several cardiovascular risk factors, albuminuric mild to moderate chronic kidney disease or heart failure. Current guidelines proposed a new paradigm in the management of T2DM, with a preferential place for SGLT2is, after metformin, in patients with atherosclerotic cardiovascular disease, heart failure and progressive kidney disease. Ongoing trials might extend the therapeutic potential of SGLT2is in patients with, but also without, T2DM. This Review provides an update of the current knowledge on SGLT2is, moving from their use as glucose-lowering medications to their new positioning as cardiovascular and renal protective agents.

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Section: Box 1 | Sodium-glucose Cotransporter Type 2 Inhibitorsmentioning

confidence: 99%

Section: Box 1 | Sodium-glucose Cotransporter Type 2 Inhibitorsmentioning

confidence: 99%

Sodium–glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus

Scheen

2020

Nat Rev Endocrinol

188

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“…A potential mechanism may be that since phosphate and glucose transporters use the same sodium gradient, these transporters may limit each other [ 84 ]. Because SGLT2 inhibitors prevent the cotransport and reabsorption of sodium and glucose, the sodium gradient is preserved for the sodium-dependent phosphate transport proteins NaPi-2a and NaPi-2c, stimulating tubular phosphate reabsorption [ 85 ]. Despite these small effects on mineral metabolism, SGLT2 inhibitors have shown clinically relevant cardiovascular and renal protective effects in diabetic nephropathy, without convincing adverse effects on the bone [ 85 •].…”

Section: Fgf23-reducing Strategiesmentioning

confidence: 99%

“…Because SGLT2 inhibitors prevent the cotransport and reabsorption of sodium and glucose, the sodium gradient is preserved for the sodium-dependent phosphate transport proteins NaPi-2a and NaPi-2c, stimulating tubular phosphate reabsorption [ 85 ]. Despite these small effects on mineral metabolism, SGLT2 inhibitors have shown clinically relevant cardiovascular and renal protective effects in diabetic nephropathy, without convincing adverse effects on the bone [ 85 •]. As mentioned before, insulin seems capable to reduce FGF23 levels in human and mice [ 31 ]; the clinical value of this observation should be further addressed.…”

Section: Fgf23-reducing Strategiesmentioning

confidence: 99%

Fibroblast Growth Factor 23 and Adverse Clinical Outcomes in Type 2 Diabetes: a Bitter-Sweet Symphony

et al. 2020

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Purpose of Review Fibroblast growth factor 23 (FGF23) is a key phosphate-regulating hormone that has been associated with adverse outcomes in patients with chronic kidney disease (CKD). Emerging data suggest that FGF23 plays a specific role in type 2 diabetes, partly independent of kidney function. We aimed to summarize current literature on the associations between FGF23 and outcomes in patients with type 2 diabetes with or without CKD. Recent Findings Several cohort studies have shown strong associations between plasma FGF23 and cardiovascular outcomes in diabetic CKD. Moreover, recent data suggest that FGF23 are elevated and may also be a risk factor for cardiovascular disease and mortality in type 2 diabetes patients without CKD, although the magnitude of the association is smaller than in CKD patients. Summary Diabetes-related factors may influence plasma FGF23 levels, and a higher FGF23 levels seem to contribute to a higher cardiovascular and mortality risk in patients with type 2 diabetes. Although this risk may be relevant in diabetic individuals with preserved kidney function, it is strongly accentuated in diabetic nephropathy. Future studies should clarify if FGF23 is merely a disease severity marker or a contributor to adverse outcomes in type 2 diabetes and establish if antidiabetic medication can modify FGF23 levels.

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“…SGLT2 inhibitors might indirectly increase bone turnover by weight loss. Determining the relevance of the effect of SGLT2 inhibitors on bone fractures and mineral metabolism in T2D, however, requires further investigation [189].…”

Section: Safety Of Sglt2 Inhibitors and Adverse Effectsmentioning

confidence: 99%

Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: from molecular discovery to clinical application

Gyimesi

Pujol‐Giménez

Kanai

et al. 2020

Pflugers Arch - Eur J Physiol

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Sodium glucose transporters (SGLTs) belong to the mammalian solute carrier family SLC5. This family includes 12 different members in human that mediate the transport of sugars, vitamins, amino acids, or smaller organic ions such as choline. The SLC5 family belongs to the sodium symporter family (SSS), which encompasses transporters from all kingdoms of life. It furthermore shares similarity to the structural fold of the APC (amino acid-polyamine-organocation) transporter family. Three decades after the first molecular identification of the intestinal Na +-glucose cotransporter SGLT1 by expression cloning, many new discoveries have evolved, from mechanistic analysis to molecular genetics, structural biology, drug discovery, and clinical applications. All of these advances have greatly influenced physiology and medicine. While SGLT1 is essential for fast absorption of glucose and galactose in the intestine, the expression of SGLT2 is largely confined to the early part of the kidney proximal tubules, where it reabsorbs the bulk part of filtered glucose. SGLT2 has been successfully exploited by the pharmaceutical industry to develop effective new drugs for the treatment of diabetic patients. These SGLT2 inhibitors, termed gliflozins, also exhibit favorable nephroprotective effects and likely also cardioprotective effects. In addition, given the recent finding that SGLT2 is also expressed in tumors of pancreas and prostate and in glioblastoma, this opens the door to potential new therapeutic strategies for cancer treatment by specifically targeting SGLT2. Likewise, further discoveries related to the functional association of other SGLTs of the SLC5 family to human pathologies will open the door to potential new therapeutic strategies. We furthermore hope that the herein summarized information about the physiological roles of SGLTs and the therapeutic benefits of the gliflozins will be useful for our readers to better understand the molecular basis of the beneficial effects of these inhibitors, also in the context of the tubuloglomerular feedback (TGF), and the renin-angiotensin system (RAS). The detailed mechanisms underlying the clinical benefits of SGLT2 inhibition by gliflozins still warrant further investigation that may serve as a basis for future drug development.

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Effects of sodium glucose cotransporter 2 inhibitors on mineral metabolism in type 2 diabetes mellitus

Cited by 19 publications

References 47 publications

Sodium–glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus

Sodium–glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus

Fibroblast Growth Factor 23 and Adverse Clinical Outcomes in Type 2 Diabetes: a Bitter-Sweet Symphony

Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: from molecular discovery to clinical application

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