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The nephrological perspective on SGLT-2 inhibitors in type 1 diabetes.
Gillard, P, Schnell, O, Groop, PH
Diabetes research and clinical practice. 2020;:108462
Abstract
Prevalence of type 1 diabetes mellitus (T1DM) is globally continuously increasing. T1DM is accompanied by a high risk of developing cardiovascular and renal comorbidities and is one of the leading causes of end-stage renal disease (ESRD). However, current therapeutic approaches for chronic and/or diabetic kidney disease (CKD/DKD) existed for a long time, and offer room for improvement, particularly in T1DM. In 2019, the European Medicines Agency (EMA) approved a first sodium/glucose co-transporter 2 inhibitor (SGLT-2i) and a first dual SGLT-1/-2i to improve glycaemic control, as an adjunctive treatment to insulin in persons with T1DM and a body mass index ≥27 kg/m2. Of note, SGLT-1/2is and SGLT-2is are not approved by the Food and Drug Administration (FDA) as an adjunct treatment in T1DM, nor approved for the treatment of CKD or DKD by EMA and FDA. SGLT is have shown to mediate different renoprotective effects in type 2 diabetes mellitus in corresponding cardiovascular and renal outcome trials. First efficacy trials offer insights into potential positive effects on renal function and kidney disease of SGLTis in T1DM. This review summarizes and discusses latest available data on SGLT inhibition and provides an update on the nephrological perspective on SGLTis, specifically in T1DM.
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[SGLT2 inhibitors, beyond glucose-lowering effect: impact on nephrology clinical practice].
Costanza, G, Pesce, F, Forcella, M, Leonardi, G, Seminara, G, Di Natale, E, Granata, A
Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia. 2020;(4)
Abstract
Epidemiological data show an increasing diffusion of diabetes mellitus worldwide. In the diabetic subject, the risk of onset of chronic kidney disease (CKD) and its progression to the terminal stage remain high, despite current prevention and treatment measures. Although SGLT2 inhibitors have been approved as blood glucose lowering drugs, they have shown unexpected and surprising cardioprotective and nephroprotective efficacy. The multiple underlying mechanisms of action are independent and go beyond glycemic lowering. Hence, it has been speculated to extend the use of these drugs also to subjects with advanced stages of CKD, who were initially excluded because of the expected limited glucose-lowering effect. Non-diabetic patients could also benefit from the favorable effects of SGLT2 inhibitors: subjects with renal diseases with different etiologies, heart failure, high risk or full-blown cardiovascular disease. In addition, these drugs have a good safety profile, but several post-marketing adverse event have been reported. The ongoing clinical trials will provide clearer information on efficacy, strength and safety of these molecules. The purpose of this review is to analyze the available evidence and future prospects of SGLT2 inhibitors, which could be widely used in nephrology clinical practice.
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Primary versus secondary cardiorenal prevention in type 2 diabetes: Which newer anti-hyperglycaemic drug matters?
Giugliano, D, Ceriello, A, De Nicola, L, Perrone-Filardi, P, Cosentino, F, Esposito, K
Diabetes, obesity & metabolism. 2020;(2):149-157
Abstract
We are observing a resurgence of major diabetic vascular complications after a period of dramatic decrease during the period 1990 to 2010. The classical division of cardiovascular prevention into primary (with an event) and secondary (without an event) is largely used to describe cardiovascular risk in type 2 diabetes (T2D); however, there is evidence that the cardiovascular risk in diabetes may range from highest in patients who experienced a previous cardiovascular event to mild in patients with the main risk factors at target. Herein, we present details of the 14 cardiovascular outcome trials (CVOTs) published to date, including the total population investigated, and their separation into primary (T2D + multiple risk factors) and secondary prevention (T2D + established cardiovascular disease [CVD]) populations as detailed within the trials. We also summarize evidence for the effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium glucose co-transporter-2 inhibitors (SGLT-2i) versus placebo on the risk of major cardiovascular events (MACE), heart failure (HF) and diabetic kidney disease (DKD). In primary prevention, SGLT-2i reduce both the risk of hospitalization for HF and progression of DKD; in secondary prevention, SGLT-2i are effective on the three endpoints, DPP-4i are neutral, while GLP1-RA show mixed results.
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Efficacy and safety profile of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease.
Scheen, AJ
Expert opinion on drug safety. 2020;(3):243-256
Abstract
Introduction: Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) have a complex relationship with the kidney so that their use in patients with type 2 diabetes (T2DM) and diabetic kidney disease (DKD) has long been challenged.Areas covered: SGLT2is in patients with DKD are discussed: renal mechanisms of action, PK/PD characteristics, clinical use in patients with stage 3 DKD, effects on estimated glomerular filtration rate (eGFR) and albuminuria, cardiovascular, and renal outcomes according to renal function, overall and renal safety, SGLT2is new place in updated guidelines.Expert opinion: Whereas initial concerns (reduced glucose-lowering efficacy, early reduction in eGFR) led to restrictions in the use of SGLT2is in patients with DKD, recent positive observations have completely reversed the scene. Indeed, albuminuria is reduced and eGFR is preserved in the long term by SGLT2is. A significant reduction in cardiovascular events and hard renal outcomes was reported even in patients with eGFR 30-60 mL/min/1.73 m2. The overall safety profile of SGLT2is is not altered in patients with mild to moderate DKD, with a reduced (rather than increased) risk of acute renal injury. This positive benefit/risk balance led recent guidelines to recommend SGLT2is in patients with T2DM and mild to moderate DKD, especially if albuminuria.
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Are low-carbohydrate diets safe in diabetic and nondiabetic chronic kidney disease?
Mitchell, NS, Scialla, JJ, Yancy, WS
Annals of the New York Academy of Sciences. 2020;(1):25-36
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Abstract
Diabetes mellitus and obesity both contribute to chronic kidney disease (CKD) and diabetic kidney disease (DKD), and they can accelerate the loss of kidney function. Dietary intake can potentially have wide-reaching effects on the risk of CKD/DKD and their progression by reducing weight and blood pressure, improving glycemic control, reducing hyperfiltration, and modulating inflammation. Low-carbohydrate (LC) diets can reduce weight and improve glycemic control, but the relatively higher protein content also raises concern in CKD/DKD. Empiric evidence supporting the kidney-related benefits or risks of LC diets is needed to understand the balance of these potential harms and benefits for patients with DKD and is the subject of our review.
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[The heart and kidney in diabetes: Heart and kidney in diabetes].
Tejedor, A
Hipertension y riesgo vascular. 2020;(2):64-71
Abstract
The diabetic kidney presents excess expression and activity of the SGLT2 transporter of the proximal tubule. This situation increases the renal reabsorption of Na and glucose and reduces their distal supply. In addition to the metabolic effects on the internal environment of this excess reabsorbed glucose, the renal tubule is subjected to glycosylated stress capable of locally activating both apoptosis and inflammasome. The result is a progressive loss of nephron units, activation of transition of mesangial epithelium and collagen deposition. Activation of insulin signalling by the MAP kinase pathway and resistance to the metabolic effects of insulin take place. This is simultaneously combined with afferent vasodilation due to hyperglycaemia, tubuloglomerular feedback inhibition due to reduced distal fluid supply, podocyte dedifferentiation and reduction in their number, the latter effects being due to insulin resistance. The result is self-feeding renal damage, with intraglomerular hyper-pressure, podocyte dedifferentiation, tubular apoptosis, and local and distant activation of inflammasome. All these effects are susceptible to be totally or partially corrected by inhibiting glucose transport via the SGLT transporters.
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The tubular hypothesis of nephron filtration and diabetic kidney disease.
Vallon, V, Thomson, SC
Nature reviews. Nephrology. 2020;(6):317-336
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Abstract
Kidney size and glomerular filtration rate (GFR) often increase with the onset of diabetes, and elevated GFR is a risk factor for the development of diabetic kidney disease. Hyperfiltration mainly occurs in response to signals passed from the tubule to the glomerulus: high levels of glucose in the glomerular filtrate drive increased reabsorption of glucose and sodium by the sodium-glucose cotransporters SGLT2 and SGLT1 in the proximal tubule. Passive reabsorption of chloride and water also increases. The overall capacity for proximal reabsorption is augmented by growth of the proximal tubule, which (alongside sodium-glucose cotransport) further limits urinary glucose loss. Hyperreabsorption of sodium and chloride induces tubuloglomerular feedback from the macula densa to increase GFR. In addition, sodium-glucose cotransport by SGLT1 on macula densa cells triggers the production of nitric oxide, which also contributes to glomerular hyperfiltration. Although hyperfiltration restores sodium and chloride excretion it imposes added physical stress on the filtration barrier and increases the oxygen demand to drive reabsorption. Tubular growth is associated with the development of a senescence-like molecular signature that sets the stage for inflammation and fibrosis. SGLT2 inhibitors attenuate the proximal reabsorption of sodium and glucose, normalize tubuloglomerular feedback signals and mitigate hyperfiltration. This tubule-centred model of diabetic kidney physiology predicts the salutary effect of SGLT2 inhibitors on hard renal outcomes, as shown in large-scale clinical trials.
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Combination therapy with SGLT2 inhibitors for diabetic kidney disease.
Cai, Y, Liu, X, Xu, G
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2020;:110192
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of oral antihyperglycemic agents developed in recent years. They could block most glucose reabsorption in renal proximal tubules, thereby exerting glucose lowering effects through glycosuric ways. The renal and cardiovascular protection effects of SGLT2 inhibitors have also been demonstrated both in preclinical studies and clinical trials. However, SGLT2 inhibitors alone could induce an increase in endogenous/hepatic glucose production as well as in fasting plasma glucose levels; a sharp decrease of blood glucose concentration induced by SGLT2 inhibitors could also promote the secretion of counter-regulatory hormones such as glucagon, which has been reported to be associated with the occurrence of glycemic ketoacidosis. Therefore, coadministration of SGLT2 inhibitors and other antihyperglycemic agents should be considered when the therapeutic effect of SGLT2 inhibitors alone was unsatisfactory.
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How Low Do We Go (in the Post-SPRINT Era)?
Burgner, A, Lewis, JB
Advances in chronic kidney disease. 2019;(2):110-116
Abstract
Hypertension is frequently both a cause and complication of CKD. The optimal blood pressure target in CKD has been of hot debate over the decades with little data to inform the goals. Here, we review the data from the Systolic Blood Pressure Intervention Trial (SPRINT), Modification of Diet in Renal Disease (MDRD), African American Study of Kidney Disease and Hypertension (AASK), Ramipril Efficacy in Nephropathy-2 (REIN-2), and Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials to use the available evidence to better inform what blood pressure goal should be recommended in patients with CKD and to answer the question "How low should we go?".
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Nonproteinuric progressive diabetic kidney disease.
Zoccali, C, Mallamaci, F
Current opinion in nephrology and hypertension. 2019;(3):227-232
Abstract
PURPOSE OF REVIEW We will summarize recent epidemiological observations on the risk for overt diabetic kidney disease (DKD) in nonproteinuric patients, will focus on novel studies based on a proteomic biomarker of DKD and will discuss the possibility of preventing the progression of DKD in nonproteinuric patients by sodium glucose transporter 2 (SGLT2) inhibitors. RECENT FINDINGS Although less frequently than in type 2 diabetes, DKD may develop also in nonproteinuric type 1 diabetes. However, the progression rate to kidney failure in nonproteinuric diabetic people is much lower than in proteinuric ones. A new proteomic biomarker, the chronic kidney disease (CKD)273, reliably predicts the risk of incident micro and macroalbuminuria and of CKD in nonalbuminuric diabetic people. SGLT2 inhibition markedly reduces albuminuria in macro and microalbuminuric patients and discernibly mitigates albumin excretion also in those with albuminuria in the normal range. SUMMARY Studies focusing on risk factors for DKD in nonproteinuric patients are a clinical research priority. The CKD273 classifier is a promising biomarker for the early identification of nonproteinuric patients at high risk for progressive DKD. Empagliflozin and SGLT2 inhibitors may have a favorable impact on the progression of DKD in nonalbuminuric diabetic people, a hypothesis to be tested in specific clinical trials.