SGLT2 Inhibitors: Nephroprotective Efficacy and Side Effects

Garofalo, Carlo; Borrelli, Silvio; Liberti, Maria Elena; Andreucci, Michele; Conte, Giuseppe; Minutolo, Roberto; Provenzano, Michele; Nicola, Luca De

doi:10.3390/medicina55060268

Cited by 63 publications

(57 citation statements)

References 78 publications

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“…In children with fatty acid oxidation defects such as multiple acyl-CoA dehydrogenase deficiency, D+L-BHB improved heart function and cognitive performance, which resulted in better walking ability and correction of neurological symptoms (37). Moreover, clinical trials in diabetes with sodium/glucose co-transporter-2 (SGLT-2) inhibitors, which increase plasma ketones (38), show markedly reduced risk of cardiovascular events and kidney failure (39). Given the significant dysregulation of energy metabolism in type 2 diabetes, it is plausible that part of the effect of SGLT2 inhibitors on heart and kidney is mediated via improved ATP production using ketones as an alternative energy fuel to fatty acid and glucose (38,40).…”

Section: Mct (Based On Iauc Over 4 H)mentioning

confidence: 99%

Metabolism of Exogenous D-Beta-Hydroxybutyrate, an Energy Substrate Avidly Consumed by the Heart and Kidney

et al. 2020

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There is growing interest in the metabolism of ketones owing to their reported benefits in neurological and more recently in cardiovascular and renal diseases. As an alternative to a very high fat ketogenic diet, ketones precursors for oral intake are being developed to achieve ketosis without the need for dietary carbohydrate restriction. Here we report that an oral D-beta-hydroxybutyrate (D-BHB) supplement is rapidly absorbed and metabolized in humans and increases blood ketones to millimolar levels. At the same dose, D-BHB is significantly more ketogenic and provides fewer calories than a racemic mixture of BHB or medium chain triglyceride. In a whole body ketone positron emission tomography pilot study, we observed that after D-BHB consumption, the ketone tracer 11 C-acetoacetate is rapidly metabolized, mostly by the heart and the kidneys. Beyond brain energy rescue, this opens additional opportunities for therapeutic exploration of D-BHB supplements as a "super fuel" in cardiac and chronic kidney diseases.

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Section: Mct (Based On Iauc Over 4 H)mentioning

confidence: 99%

Metabolism of Exogenous D-Beta-Hydroxybutyrate, an Energy Substrate Avidly Consumed by the Heart and Kidney

et al. 2020

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“…Hence, the CV risk effect of novel antialbuminuric drugs has been tested (Bolignano et al, 2015;Leporini et al, 2016). For this aim, Sodiumglucose cotransporter 2 (SGLT-2) inhibitors are promising agents (Savarese et al, 2014;Wanner et al, 2016;Coppolino et al, 2018b;Garofalo et al, 2019). SGLT-2 inhibitors act by reducing the reabsorption of glucose in the renal proximal tubule (Garofalo et al, 2019).…”

Section: Strategies For Reducing Cardiovascular Risk In Chronic Kidnementioning

confidence: 99%

“…For this aim, Sodiumglucose cotransporter 2 (SGLT-2) inhibitors are promising agents (Savarese et al, 2014;Wanner et al, 2016;Coppolino et al, 2018b;Garofalo et al, 2019). SGLT-2 inhibitors act by reducing the reabsorption of glucose in the renal proximal tubule (Garofalo et al, 2019). They determine both hemodynamic and nonhemodynamic changes in the kidney, the first being mainly represented by the reduction in intraglomerular pressure and eGFR through tubuloglomerular feedback, whereas the second by a consistent reduction in oxidant stress (up to 60%), a reduction in NLRP3 inflammasome activity and an increase in intrarenal angiotensinogen levels (De Nicola et al, 2014;Bakris, 2019).…”

Section: Strategies For Reducing Cardiovascular Risk In Chronic Kidnementioning

confidence: 99%

Unraveling Cardiovascular Risk in Renal Patients: A New Take on Old Tale

Provenzano

Coppolino

Nicola

et al. 2019

Front. Cell Dev. Biol.

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Chronic kidney disease (CKD), defined by an estimated glomerular filtration rate <60 ml/min/1.73 m 2 and/or an increase in urine protein excretion (i.e., albuminuria), is an important public health problem. Prevalence and incidence of CKD have risen by 87 and 89%, worldwide, over the last three decades. The onset of either albuminuria and eGFR reduction has found to predict higher cardiovascular (CV) risk, being this association strong, independent from traditional CV risk factors and reproducible across different setting of patients. Indeed, this relationship is present not only in high risk cohorts of CKD patients under regular nephrology care and in those with hypertension or type 2 diabetes, but also in general, otherwise healthy population. As underlying mechanisms of damage, it has hypothesized and partially proved that eGFR reduction and albuminuria can directly promote endothelial dysfunction, accelerate atherosclerosis and the deleterious effects of hypertension. Moreover, the predictive accuracy of risk prediction models was consistently improved when eGFR and albuminuria have been added to the traditional CV risk factors (i.e., Framingham risk score). These important findings led to consider CKD as an equivalent CV risk. Although it is hard to accept this definition in absence of additional reports from scientific Literature, a great effort has been done to reduce the CV risk in CKD patients. A large number of clinical trials have tested the effect of drugs on CV risk reduction. The targets used in these trials were different, including blood pressure, lipids, albuminuria, inflammation, and glucose. All these trials have determined an overall better control of CV risk, performed by clinicians. However, a non-negligible residual risk is still present and has been attributed to: (1) missed response to study treatment in a consistent portion of patients, (2) role of many CV risk factors in CKD patients not yet completely investigated. These combined observations provide a strong argument that kidney measures should be regularly included in individual prediction models for improving CV risk stratification. Further studies are needed to identify high risk patients and novel therapeutic targets to improve CV protection in CKD patients.

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“…In conclusion, better knowledge of risk factors, diagnosis, and treatment of euDKA likely represent an essential step to translate the cardiorenal protective efficacy of SGLT2-I proven in RCTs [16] into full effectiveness in the real world of daily clinical practice. This case report suggests the need of more active involvement of nephrologist in the prevention and management of this critical event.…”

Section: Discussionmentioning

confidence: 99%

Nephrology Consultation for Severe SGLT2 Inhibitor-Induced Ketoacidosis in Type 2 Diabetes: Case Report

Nappi¹,

Verde

Carfora

et al. 2019

Medicina

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Euglycemic diabetic ketoacidosis (euDKA) related to sodium-glucose cotransporter 2 inhibitor (SGLT2-I), despite being reported as consistent, though infrequent, adverse effect in all trials on SGLT2-I in type 2 diabetes mellitus (T2D), still remains poorly known in the real world. On the other hand, the use of this new class of antihyperglycemic agents is expected to increase based on the recent solid evidence of remarkable cardiorenal protection. Therefore, improving awareness on risk factors, diagnosis, and treatment of euDKA is essential to allow correct implementation of SGLT2-I in clinical practice. We here report a T2D patient admitted to the emergency department and then transferred to the nephrology-dialysis unit because of severe euglycemic diabetic ketoacidosis (euDKA) related to sodium-glucose cotransporter 2 inhibitor (SGLT2-I). In our patient, a concurrent acute kidney injury at presentation, initially attributed to excessive use of nonsteroid anti-inflammatory agents, and the absence of severe hyperglycemia led to delayed diagnosis and proper therapy. The detailed description of decision-making process for diagnosis and therapy, and the analysis of precipitating factors as well, discloses the helpful contribution of nephrologist to optimize prevention and management of euDKA.

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SGLT2 Inhibitors: Nephroprotective Efficacy and Side Effects

Cited by 63 publications

References 78 publications

Metabolism of Exogenous D-Beta-Hydroxybutyrate, an Energy Substrate Avidly Consumed by the Heart and Kidney

Metabolism of Exogenous D-Beta-Hydroxybutyrate, an Energy Substrate Avidly Consumed by the Heart and Kidney

Unraveling Cardiovascular Risk in Renal Patients: A New Take on Old Tale

Nephrology Consultation for Severe SGLT2 Inhibitor-Induced Ketoacidosis in Type 2 Diabetes: Case Report

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