SGLT2 inhibitors, beyond glucose-lowering effect: impact on nephrology clinical practice

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.

Keywords: diabetes, oral hypoglycemic agents, SGLT2 inhibitors, chronic kidney disease

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Introduzione

Il diabete mellito (DM) è una delle patologie più diffuse nel mondo: ne soffre circa l’8,5% della popolazione adulta ed il trend nelle ultime decadi mostra un progressivo aumento dell’incidenza e della prevalenza [1].

La malattia renale cronica (MRC) è frequente complicanza del DM, sia di tipo 1 (DM1) che di tipo 2 (DM2). Si calcola che tra il 40 e il 50% dei soggetti affetti da DM2 sviluppa MRC nell’arco della vita e la sua presenza e severità influenzano significativamente la prognosi [2, 3, 4]. Pochi e dibattuti sono i dati relativi alla progressione del danno renale nel diabetico fino alla malattia renale cronica terminale (ESRD). Le cifre sono sottostimate e inficiate dall’elevata mortalità di questi soggetti, molti dei quali muoiono prima di giungere alla necessità di terapia sostitutiva della funzione renale, soprattutto per patologie cardiovascolari (CV) [5, 6, 7]. Negli Stati Uniti nel 2010 la prevalenza di ESRD tra i diabetici adulti è stata di 20/10.000 [8]. Guardando all’eziopatogenesi, il DM è ormai stabilmente la causa principale dell’ESRD. È da ascrivere al DM il 23% e il 16% dei casi incidenti e prevalenti di ESRD, rispettivamente, secondo il più recente report ERA-EDTA (European Renal Association-European Dialysis and Transplant Association) [9]. 

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Metformin and Diabetes: still has a sense of its use in paz. CKD stage II or is an additional risk factor?

Abstract

Pz woman of 62 years comes to P.S.G. for fatigue, low-grade fever, diuresis present. A history of hypertension refers to therapy for about five years, diabetes mellitus for about two years in therapy with Metformin 1gr x 3 gg / day.  Blood tests: BUN 195 mg / dL, creatinine 8.0 mg / dl, Ph 6877, HCO3 5.1 mmol / L BE -29.1 mmol / l. Rapid clinical deterioration with occurrence of arterial hypotension – 85/60 mmHg, stupor. Start therapy Bicarbonates ev, is positioned in Urgency CVC and it undergoes AFB with infusion of bicarbonates 2000 ml / h for 4 hours, blood flow rate 250 ml / min., the hemodynamics has been supported with dopamine infusion 200 mg: 2 vials in 250 cc of physiological vel 30 – 40 ml / h, The pc after undergoing three AFB, interrupted the dialysis for resumption of diuresis spontaneous and progressive improvement of renal function and blood pressure. Monitored, after discharge, the parameters of renal function decreased to within normal limits, clearance compatible with IRC II – III stage.

Conclusions: dehydration, fever, IRC II stadium, undiagnosed caused, in a very short time, an accumulation of metformin, which has been the cause of metabolic acidosis. The pc. saved thanks to the positioning of the CVC and to the AFB in the treatment with the infusion of large quantities of Bicarbonates e.v.

The use of metformin in pcs. > 50 years and / or creatinine clearance <60 ml / min., Must be subordinated to the preliminary study and periodic renal function.

 

Keywords: Metformin, Diabetes, IRA, metabolic acidosis

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Paziente di sesso femminile di 62 anni giunge al P.S.G. per astenia, malessere generale e riferita febbricola, in anamnesi riferisce ipertensione arteriosa in terapia antipertensiva da circa 5 anni, diabete mellito non insulino dipendente da circa 2 anni in terapia con Metformina 1 gr x 3/die. 

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DPP-4 inhibitors in nephropatics

Abstract

The use of glucose-lowering drugs in advanced stage diabetic nephropathic patients should be done very carefully. Some drugs are contraindicated or not recommended. The same insulin needs a dose reduction to avoid dangerous hypoglycemia. For some years the use of inhibitors of the DDP-4 has been approved in T2DM patients with CKD III and IV stage, proposing the use without limitations even in case of ESRD.

We conducted a prospective observational study of a cohort of 60 patients with T2DM and CKD stage IV, selecting a sample of 15 patients taking an inhibitor of DPP-4 and comparing it with those who took therapy “old” drugs, despite having similar characteristics of CKD.

In both groups, we found: 1) the effectiveness of therapy, through the assessment of glycated hemoglobin and glycemic profile; 2) the possible occurrence of “hypoglycemia”, “side effects”, accelerating the progression of CKD. No patients being treated with inhibitors of DPP-4 have experienced hypoglycemia, or adverse events, or adverse effects on the progression of CKD. The glycated hemoglobin, revealed more stability than the comparison group. Hypoglycaemic episodes were present only in the group receiving intensive insulin. Although kidneys and their dose, in case of high degree of CKD, primarily eliminate inhibitors of DPP-4, with some exceptions, should be reduced, in our experience they have proven beneficial drugs in diabetics with kidney disease, being effective and well tolerated in the case of ESRD, where the only treatment option was represented by insulin.

Keywords: diabetes, chronic kidney disease, drug, tollerability

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Introduzione

La gestione terapeutica del paziente diabetico con Chronic Kidney Disease (CKD) è generalmente complessa. Uno degli aspetti da tenere in grande considerazione è che la terapia farmacologica ipoglicemizzante va rapportata al grado di funzionalità renale residua e va adattata “su misura” al singolo paziente. Alcuni farmaci ipoglicemizzanti orali sono controindicati nelle fasi avanzate della CKD, come la metformina, o vengono sconsigliati, come nel caso delle sulfaniluree, per il potenziale rischio di ipoglicemie da “accumulo”. Anche la stessa terapia insulinica necessita di una riduzione del dosaggio nelle fasi avanzate della insufficienza renale cronica, per evitare pericolose crisi ipoglicemiche [1, 2]. 

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