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ACE and SGLT2 inhibitors: the future for non-diabetic and diabetic proteinuric renal disease
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ScienceDirect ACE and SGLT2 inhibitors: the future for non-diabetic and diabetic proteinuric renal disease Norberto Perico1, Piero Ruggenenti1,2 and Giuseppe Remuzzi1,2,3 Most chronic nephropathies progress relentlessly to end-stage kidney disease. Research in animals and humans has helped our understanding of the mechanisms of chronic kidney disease progression. Current therapeutic strategies to prevent or revert renal disease progression focus on reduction of urinary protein excretion and blood pressure control. Blockade of the renin-angiotensin system (RAS) with angiotensinconverting enzyme inhibitors and/or angiotensin II type 1 receptor blockers is the most effective treatment to achieve these purposes in non-diabetic and diabetic proteinuric renal diseases. For those individuals in which nephroprotection by RAS blockade is only partial, sodium–glucose linked cotransporter-2 (SGLT2) inhibitors could be a promising new class of drugs to provide further renoprotective benefit when added on to RAS blockers. Addresses 1 IRCCS—Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo & Cele Dacco`, Bergamo, Italy 2 Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy 3 Department of Biomedical and Clinical Sciences “L. Sacco”, University of Milan, Milan, Italy
to be 1.2 million, a 32% increase from 2005, with deaths from diabetic and hypertensive kidney disease comprising over 75% of these deaths [2]. The prevalence of endstage kidney disease (ESKD) patients worldwide receiving renal replacement therapy (RRT) with maintenance dialysis has also increased 1.7 times from 165 patients per million population (pmp) in 1990 to 284 pmp in 2010 [3]. ESKD is only the tip of the iceberg. While the prevalence of CKD remains ill-defined, especially in low- and middle-income countries [4], it is estimated that more than 322 million individuals are currently affected by CKD worldwide [5]. With a population that is ageing, steep increases in the incidence of type 2 diabetes mellitus and hypertension globally are driving the growth in CKD burden, putting an enormous burden on health care resources [1]. Kidney disease is therefore a global public health priority. Given the very high individual and societal cost of RRT with dialysis or transplantation, efforts to prevent or halt renal disease progression are of utmost importance to reduce the clinical and economic consequences of CKD.
Progressive nature of chronic kidney disease Corresponding author: Remuzzi, Giuseppe ([email protected])
Current Opinion in Pharmacology 2017, 33:34–40 This review comes from a themed issue on Cardiovascular and renal Edited by David A Taylor, Robert J Theobald, Abdel A Abdel-Rahman and Ethan J Anderson
http://dx.doi.org/10.1016/j.coph.2017.03.006 1471-4892/ã 2017 Elsevier Ltd. All rights reserved.
Chronic kidney disease: a global health problem Chronic kidney disease (CKD) is a key determinant of poor health outcomes for major non-communicable diseases, and has a risk-multiplier effect on cardiovascular diseases (CVD) [1]. Recent findings from the Global Burden of Disease studies have highlighted CKD as an important cause of global mortality [2]. In 2015, the number of reported deaths due to CKD was estimated Current Opinion in Pharmacology 2017, 33:34–40
Most chronic nephropathies progress relentlessly to ESKD. Research in animals and humans has helped our understanding of the mechanism of CKD progression. These studies have established that most renal diseases progress to renal failure as a consequence of functional adaptations intervening in the kidney, after the original disease process causes an initial loss of nephron units [6]. Such changes, extensively studied in rodents, include glomerular hyperperfusion, and hypertension of the remaining nephrons, which begin with enhancing the filtration capacity of single nephrons. These changes initially minimize the functional consequences of nephron loss but eventually become detrimental, contributing to the impairment of the glomerular barrier’s size selective properties and inducing protein ultrafiltration. An excess of protein contents in Bowman’s space and in the lumen of tubules ultimately results in the activation of inflammatory and apoptotic pathways, fuelling progressive renal damage [6]. As shown by in-vitro and in-vivo studies, the activation of a variety of cytokines, growth factors and vasoactive substances may result in abnormal accumulation in the mesangium and in the tubulo-interstitium of extracellular matrix collagen, fibronectin and other components that are responsible for glomerulosclerosis and interstitial fibrosis and progressive renal injury [6] (Figure 1). www.sciencedirect.com
ACE and SGLT2 inhibitors: the future for non-diabetic and diabetic proteinuric renal disease Perico, Ruggenenti and Remuzzi 35
Figure 1
Degenerative/inflammatory glomerular diseases
Interstitium Proximal tubular cell
Nephron loss
ET-1 MCP-1 mRNA Fractalkine RANTES
Lymphocyte/macrophage infiltration
Compensatory glomerular capillary hypertension pore dimension
ET-1 MCP-1 Fractalkine RANTES
DNA
Nuclear signals for gene transcription
Cytokines/ chemokines Interstitial fibroblasts
Proteinuria
Excessive tubular protein reabsorption
Cell proliferation
ECM ECM protein degradation synthesis
Tubular interstitial damage and inflammation DISEASE PROGRESSION Current Opinion in Pharmacology
Mechanisms of progression of proteinuric kidney disease. A reduction in the number of nephrons as a consequence of various glomerular diseases results in compensatory glomerular hemodynamic changes that are ultimately detrimental. In particular, by mechanical stretching, the increased glomerular capillary pressure directly injures glomerular cells. Glomerular hypertension also impairs the glomerular capillary size-selective function which causes excessive protein ultrafiltration, and, eventually, podocyte injury and proteinuria. The intraglomerular capillary hemodynamic changes are mainly driven by increased synthesis of angiotensin II. Protein overload of proximal tubular cells as a consequence of increased glomerular permeability to proteins activates intracellular signals that promote cell apoptosis or cause increased production of inflammatory and vasoactive mediators and of growth factors. These substances are released into the interstitium, inducing progressive inflammation and injury. ECM, extracellular matrix; ET-1, endothelin-1; MCP-1, monocyte chemoattractant protein-1; RANTES, regulated upon activation, normal T cell expressed and secreted.
Renin-angiotensin system blockade for renoprotection in non-diabetic nephropathies Current strategies to prevent or revert renal disease progression focus on reduction of protein trafficking along with strict blood pressure control. Blockade of the renin-angiotensin system (RAS) by means of angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin II type 1 receptor blockers (ARBs) is the most effective treatment to achieve these purposes. Animal models of proteinuric chronic nephropathy have clearly documented that RAS inhibitors reduce intraglomerular hydraulic pressure and improve the selectivity of the glomerular barrier, an effect that translates into a reduction of proteinuria and prevention of glomerulosclerosis [7]. Similar effects have been reported on the clinical ground. In patients www.sciencedirect.com
with non-diabetic proteinuric nephropathies, the Ramipril Efficacy In Nephropathy (REIN) trial showed that, at equivalent blood pressure control, the ACEi ramipril halved the rate of glomerular filtration rate (GFR) decline, providing evidence for a nephroprotective effect of protein trafficking reduction [8]. Renoprotection was time dependent, and in patients on continued ramipril therapy for at least 5 years, the rate of GFR decline progressively improved up to 1 ml/min/1.73 m2 per year, approximating the physiological age-related loss of GFR with time in individuals with no evidence of renal disease [9]. There is also indirect evidence that in humans regression of CKD is achievable with ACEi therapy [10]. In ten of the REIN’s study patients on ACEi, there was a break point indicating the transition from an initial phase of Current Opinion in Pharmacology 2017, 33:34–40
36 Cardiovascular and renal
progressive GFR decline to a second phase of gradual renal function improvement, possibly reflecting regression of renal lesions along with some degree of renal tissue regeneration [11]. The beneficial effect of the ACEi on GFR was paralleled by further proteinuria reduction across the break point [11]. Subsequent experimental studies in rat models have documented that amelioration of renal function achieved by chronic ACEi therapy was mediated through regression of sclerosis in most partially injured glomeruli and regeneration of renal vasculature [12,13].
ACEi or ARBs for renoprotection in diabetic kidney disease In the past two decades studies have also demonstrated the renoprotective effect of RAS blockade in patients with type 2 diabetes and nephropathy. The Reduction of Endpoints in non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial [14] and the Irbesartan in Diabetic Nephropathy Trial (IDNT) [15] showed that ARB treatment, as compared to placebo, reduced the incidence of a composite endpoint of doubling of serum creatinine concentrations, ESKD, or death by 16% and 19%, respectively, in two large cohorts of patients with type 2 diabetes and overt nephropathy. Renoprotection was associated with a significant reduction in urinary protein excretion. Independent of treatment allocation, both trials showed that an early reduction in urinary protein excretion was associated with slower renal function loss and reduced cardiovascular mortality in long-term [16]. Experimental and clinical studies have also pointed out the importance of early pharmacologic intervention in type 2 diabetic kidney diseases (DKD) to afford better renoprotection. In a rat model of streptozocin-induced diabetes, ACE inhibition provided remarkable renoprotection against the development of nephropathy, but only when treatment was started early in the course of the disease [17]. In the IRbesartan MicroAlbuminuria type 2 diabetes in hypertensive patients (IRMA-2) trial, a fulldose irbesartan therapy reduced the 2-year incidence of progression to macroalbuminuria from 14.9% to 5.2% compared to placebo and increased the rate of regression to normoalbuminuria [18]. RAS inhibition is renoprotective even when treatment is started earlier, as shown in the Bergamo Nephrologic Diabetes Complication Trial (BENEDICT) in type 2 diabetic patients with hypertension and normal urinary protein excretion rate [19]. Four years treatment with the ACEi trandolapril reduced the risk of progression to microalbuminuria from 10.9 to 5.8% compared to nonACEi therapy [19]. Interestingly, among normoalbuminuric patients, any measurable albuminuria bore significant cardiovascular risk and in those receiving ACEi therapy, the event rate was uniformly low [20]. Current Opinion in Pharmacology 2017, 33:34–40
All the above findings have been recently confirmed in a study that, modeling DKD progression in large cohorts of type 2 diabetic patients, documented a superior beneficial effect of RAS intervention in the early stages of the disease in delaying ESKD than later treatment [21].
Dual RAS blockade for renoprotection Combination therapy with ACEi and ARBs inhibits the RAS more efficiently than does each agent alone through an additive effect. Consistently, the results of a metaanalysis indicated that dual RAS blockade was associated with greater proteinuria reduction compared to ACEi or ARB monotherapy in patients with non-diabetic chronic nephropathy [22]. Concerns, however, have been raised about double RAS inhibition since combined treatment of ramipril and telmisartan increased the risk of the prespecified composite end point of any dialysis, serum creatinine doubling or death compared with either drug alone in a large study comprising 25 620 patients with atherosclerotic disease and/or diabetes with end organ damage [23]. However, the excess of adverse renal outcomes on combination therapy was largely driven by the more frequent need for short-term dialysis, conceivably a treatment-related acute effect on renal hemodynamics that is reversible upon treatment withdrawal, rather than an indication of CKD progression. Moreover, 96% of patients in this study had normo- or micro-albuminuria, pointing to limited kidney damage to halt or reverse. Debate about the role of dual agent RAS blockade in the management of CKD has recently been reignited by the results of a meta-analysis showing that ACEi and ARB combination therapy is the most effective approach to prevent ESKD in patients with DKD [24]. This treatment benefit was independent of blood pressure control, but was associated with great improvement in albuminuria [24]. The above findings can be taken to suggest that dual RAS inhibition could be a powerful tool to slow or prevent the progression of chronic proteinuric nephropathies, provided that treatment is accompanied by close monitoring of renal function and serum electrolytes, adjusting drug doses accordingly.
The need of novel treatments for renoprotection in DKD A significant cohort of patients treated with RAS blockers, however, shows only partial anti-proteinuric response, eventually heralding a progressive loss of renal function in most cases. To address this shortcoming, we have designed a response driven, individually tailored approach to these proteinuric CKD patients, the Remission Clinic program [10]. It is a multimodal intervention protocol targeting urinary proteins by dual RAS inhibition with ACEi and ARBs up-titrated to maximum tolerated doses, by intensified blood pressure control, amelioration of dyslipidemia with statins, smoking cessation, lowering salt intake and healthy lifestyle implementation in patients who have overt proteinuria despite ACEi therapy www.sciencedirect.com
ACE and SGLT2 inhibitors: the future for non-diabetic and diabetic proteinuric renal disease Perico, Ruggenenti and Remuzzi 37
[25,26]. Although largely effective in non-diabetic proteinuric nephropathies, in approximately two-thirds of type 2 diabetic patients with overt nephropathy, remission of proteinuria was not achieved through the Remission Clinic approach, and the renal risk remained elevated. These patients urgently need novel therapeutic interventions that would complement the effects of RAS blockade in order to improve clinical outcomes [27,28].
Sodium–glucose Co-transporter 2 inhibitors in DKD Novel treatment strategies for DKD are on the horizon but investigating their efficacy is still in infancy. Beside treatment with Vitamin D receptor activators [29] or selective endothelin receptor antagonists [30,31], the most attractive approach based on the current risk/benefit results is the use of selective inhibitors of the sodium– glucose cotransporter 2 (SGLT2). Increased glucose in glomerular ultrafiltrate, as it occurs in diabetes, leads to augmented glucose delivery to the proximal tubule where it is reabsorbed along with sodium largely (80–90%) by
SGLT2 and for the remaining by SGLT1 cotransporters [32,33,34]. Accordingly, selective inhibition of SGLT2, leads to substantial glycosuria, lowering blood glucose and facilitating weight loss in individuals with diabetes [32,33,34]. Apart from the ability to increase urinary glucose excretion and eventually helping to control glycemia, SGLT2 inhibitors have recently raised substantial interest for additional properties potentially relevant for renoprotection in DKD. This possibility rests on the observation that in diabetes as it occurs in normal physiologic settings, SGLT2 and SGLT1 at proximal tubule co-transport sodium (Na+) with glucose, so that Na+ delivery to the macula densa at the juxtaglomerular apparatus will diminish [33,34]. These effects reduce the tubuloglomerular feedback signal by promoting the local release of renin and angiotensin associated with inhibition of adenosine production that result in the constriction of the nearby glomerular efferent arteriole and dilation of the adjacent afferent arteriole. Thereby intraglomerular hemodynamic changes occur leading to increase in intraglomerular capillary pressure and single-nephron
Figure 2
Diabetes
Diabetes and SGLT2 inhibition SNGFR
SNGFR AA vasodilation
AA vasoconstriction
SGLT2
SGLT2
JGA
JGA
SGLT1
SGLT1 Glucose and Na reabsorption
EA vasoconstriction
Glucose and Na reabsorption
Na delivery to JGA
EA unaffected
Na delivery to JGA
Glucose excretion
Glucose excretion Current Opinion in Pharmacology
Effect of diabetes and SLGT2 inhibition on single nephron glomerular filtration rate and Na excretion. In diabetic patients with poor glycemic control, the increased glucose in the glomerular ultrafiltrate leads to augmented glucose delivery to the proximal tubule. Here glucose tubular reabsorption, along with Na+, is increased by both SGLT2 and SGLT1. Thus, Na+ delivery to macula densa (juxtaglomerular apparatus) will be diminished, eventually reducing tubuloglomerular signals (afferent arteriole vasodilation, efferent arteriole vasoconstriction), thereby increasing single nephron glomerular filtration (SNGFR). In this setting, inhibition of sodium–glucose linked cotransporter-2 (SGLT2), by reducing glucose/Na+ reabsorption in the proximal tubule, increases Na+ delivery to the macula densa, leading to afferent arteriole vasoconstriction, while leaving unaffected efferent arteriole vascular tone. Intraglomerular capillary pressure decreases, and SNGFR returns to normal. AA, afferent arteriole; EA, efferent arteriole; SGLT2 and SGLT1, sodium–glucose linked costransporter-2 and 1, respectively; JGA, juxtaglomerular apparatus; SNGFR, single nephron glomerular filtration rate.
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glomerular filtration rate (SNGFR) [33,34,35] (Figure 2). On the other hand, inhibition of SGLT2 reduces sodium reabsorption in the proximal tubule, enhances Na+ delivery to the macula densa, eventually activating the tubuloglomerular feedback and lowering SNGFR [33,34,35] (Figure 2). Attenuation of glomerular hyperfiltration would translate in prevention of long-term glomerular damage contributing to reduce the progression of DKD. A growing body of evidence in animals with experimental diabetes has indeed suggested that SGLT2 inhibition affords renal protection. These studies have shown that SGLT2 inhibitors, empagliflozin and dapagliflozin, ameliorated diabetic nephropathy by attenuating albuminuria, mesangial expansion and interstitial fibrosis via combined effects on glomerular hemodynamics and inhibition of renal inflammation and oxidative stress mostly secondary to improvement of glycemia [36–38]. These in vivo findings confirmed previous in vitro evidence that SGLT2 inhibitors attenuated inflammatory and fibrotic responses of proximal tubular epithelial cells exposed to high glucose [39]. Of note, very recently, in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, the administration of dapaglifozin ameliorated the RAS activation characteristic of this model of type 2 diabetes by down regulation of the renal expression of the angiotensin II type 2 receptor (AT1R), which may have further contributed to the renoprotective effect of this new class of drugs in these animals [40]. Clinical studies focused on renal protection in DKD are limited. Nevertheless, the existing data in type 2 diabetic patients and stages 1-3 CKD reported that SGLT2 inhibition with empagliflozin, canagliflozin, or dapagliflozin was associated with initial acute reduction in GFR, followed by GFR stabilization on the long-term [41,42,43,44]. The acute decline in GFR was reversible after drug discontinuation, suggesting that SGLT2 inhibitors are capable to ameliorate glomerular hyperfiltration [41,44,45], a major determinant of renal disease progression in diabetes [46]. In parallel with their beneficial effect on renal hemodynamics, SGLT2 inhibitors reduced albuminuria during the 24 to 52 weeks of follow-up [41,43], anticipating possible renoprotection in longer term. Indeed, the EMPA-REG study in 7020 patients with type 2 diabetes at high cardiovascular risk, has recently shown that over a median follow-up of 3.1 years empagliflozin therapy significantly slowed the progression of kidney disease and reduced the rate of clinically relevant renal events, such as doubling of serum creatinine or ESKD compared to placebo when added to standard care [47]. These results, however, have been part of the prespecified secondary objective of the EMPA-REG trial, aimed primarily to cardiovascular outcomes [48]. So far dedicated renal protection studies such as the large Current Opinion in Pharmacology 2017, 33:34–40
randomized double-blind placebo-controlled CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical EvalNCT02065791) are underway, and are uation expected to provide more insight into the renoprotective efficacy of SGLT2 inhibitors. The main shortcoming of this new class of drugs is the risk of developing mild to moderate genitourinary infections that, however, are manageable [49–52].
Conclusion In the past decades, experimental and clinical studies have clearly documented that RAS blockers are the first line treatment to limit disease progression and renal function decline in patients with proteinuric non-diabetic and diabetic nephropathies. For those individuals in which nephroprotection by RAS blockade is only partial, SGLT2 inhibitors could be a promising new class of drugs to provide further renoprotective benefit. To this respect, trials in type 2 diabetic patients using a combination of SGLT2 with ACEi or/and ARBs should be encouraged. Furthermore, given that, beyond diabetes, SGLT2 inhibition also affects renal hemodynamic, proteinuria, blood pressure, the combination of this new class of drugs with RAS blockers may also potentially provide benefit in proteinuric non-diabetic CKD. More important, however, it would be to have therapeutic interventions with combination treatment in both diabetic and non-diabetic setting started in the early stages of the disease, when more beneficial effect in delaying ESKD than later treatment is expected [21].
Conflict of interest statement Nothing declared.
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21. Schievink B, Kropelin T, Mulder S, Parving HH, Remuzzi G, Dwyer J, Vemer P, de Zeeuw D, Lambers Heerspink HJ: Early renin-angiotensin system intervention is more beneficial than late intervention in delaying end-stage renal disease in patients with type 2 diabetes. Diabetes Obes. Metab. 2016, 18:64-71. 22. Catapano F, Chiodini P, De Nicola L, Minutolo R, Zamboli P, Gallo C, Conte G: Antiproteinuric response to dual blockade of the renin-angiotensin system in primary glomerulonephritis: meta-analysis and metaregression. Am. J. Kidney Dis. 2008, 52:475-485. 23. Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, Wang X, Maggioni A, Budaj A, Chaithiraphan S et al.: Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008, 372:547-553. 24. Palmer SC, Mavridis D, Navarese E, Craig JC, Tonelli M, Salanti G, Wiebe N, Ruospo M, Wheeler DC, Strippoli GF: Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network metaanalysis. Lancet 2015, 385:2047-2056. 25. Ruggenenti P, Perticucci E, Cravedi P, Gambara V, Costantini M, Sharma SK, Perna A, Remuzzi G: Role of remission clinics in the longitudinal treatment of CKD. J. Am. Soc. Nephrol. 2008, 19:1213-1224. This article documented that a multimodal intervention protocol– the Remission Clinic program – targeting urinary proteins by dual RAS inhibition with ACEi and ARBs up-titrated to maximum tolerated doses, allowed stabilization of renal function and prevented ESKD in 56 patients with CKD and nephrotic-range proteinuria, otherwise predicted to require RRT within few years or months. 26. Vegter S, Perna A, Postma MJ, Navis G, Remuzzi G, Ruggenenti P: Sodium intake, ACE inhibition, and progression to ESRD. J. Am. Soc. Nephrol. 2012, 23:165-173. 27. Porrini E, Ruggenenti P, Mogensen CE, Barlovic DP, Praga M, Cruzado JM, Hojs R, Abbate M, de Vries AP: Non-proteinuric pathways in loss of renal function in patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2015, 3:382-391. This Personal View provides evidence sustaining the existence of different phenotypes in type 2 diabetic renal disease. In particular, it supports the notion of a non-proteinuric phenotype and discusses possible risk factors and pathways associated with type 2 diabetes 28. Chan GC, Tang SC: Diabetic nephropathy: landmark clinical trials and tribulations. Nephrol. Dial. Transplant. 2016, 31: 359-368. 29. de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, Parving HH, Pritchett Y, Remuzzi G, Ritz E et al.: Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet 2010, 376:1543-1551. 30. Mann JF, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, Viberti G: Avosentan for overt diabetic nephropathy. J. Am. Soc. Nephrol. 2010, 21:527-535. 31. Wenzel RR, Littke T, Kuranoff S, Jurgens C, Bruck H, Ritz E, Philipp T, Mitchell A: Avosentan reduces albumin excretion in diabetics with macroalbuminuria. J. Am. Soc. Nephrol. 2009, 20:655-664. 32. Vallon V, Thomson SC: Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia 2017, 60:215-225. 33. DeFronzo RA, Norton L, Abdul-Ghani M: Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat. Rev. Nephrol. 2017, 13:11-26. This is an excellent review examining the role of SGLT1 and SGLT2 in the regulation of renal glucose reabsorption, and the effect of SGLT2 inhibition on metabolic, cardiovascular, and renal function in healthy subjects and in patients with type 2 diabetes mellitus. 34. Gilbert RE: Sodium–glucose linked transporter-2 inhibitors: potential for renoprotection beyond blood glucose lowering? Kidney Int. 2014, 86:693-700. Current Opinion in Pharmacology 2017, 33:34–40
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35. Skrtic M, Cherney DZ: Sodium–glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy. Curr. Opin. Nephrol. Hypertens. 2015, 24:96-103. This review focused on preclinical and clinical data supporting the potential role of SGLT2 inhibition in the prevention of progressive diabetic nephropathy. 36. Vallon V, Gerasimova M, Rose MA, Masuda T, Satriano J, Mayoux E, Koepsell H, Thomson SC, Rieg T: SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am. J. Physiol. Renal. Physiol. 2014, 306:F194-204. 37. Gembardt F, Bartaun C, Jarzebska N, Mayoux E, Todorov VT, Hohenstein B, Hugo C: The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Am. J. Physiol. Renal. Physiol. 2014, 307:F317-F325. 38. Terami N, Ogawa D, Tachibana H, Hatanaka T, Wada J, Nakatsuka A, Eguchi J, Horiguchi CS, Nishii N, Yamada H et al.: Long-term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. PLoS One 2014, 9: e100777. 39. Panchapakesan U, Pegg K, Gross S, Komala MG, Mudaliar H, Forbes J, Pollock C, Mather A: Effects of SGLT2 inhibition in human kidney proximal tubular cells—renoprotection in diabetic nephropathy? PLoS One 2013, 8:e54442. 40. Shin SJ, Chung S, Kim SJ, Lee EM, Yoo YH, Kim JW, Ahn YB, Kim ES, Moon SD, Kim MJ et al.: Effect of sodium–glucose Cotransporter 2 inhibitor dapagliflozin, on renal reninangiotensin system in an animal model of type 2 diabetes. PLoS One 2016, 11:e0165703. 41. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, Broedl UC: Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, doubleblind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014, 2:369-384. This randomized placebo-controlled clinical trial showed that in patients with type 2 diabetes and stage 2 or 3 of CKD adding empagliflozin to standard treatment reduced glycated hemoglobin levels, body weight, blood pressure and glomerular hyperfiltration. 42. Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, Balis DA, Canovatchel W, Meininger G: Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATASU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013, 382:941-950.
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43. Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, Figueroa K, Wajs E, Usiskin K, Meininger G: Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes. Metab. 2013, 15:463-473. 44. Kovacs CS, Seshiah V, Swallow R, Jones R, Rattunde H, Woerle HJ, Broedl UC: Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes. Metab. 2014, 16:147-158. 45. Yamout H, Perkovic V, Davies M, Woo V, de Zeeuw D, Mayer C, Vijapurkar U, Kline I, Usiskin K, Meininger G et al.: Efficacy and safety of canagliflozin in patients with type 2 diabetes and stage 3 nephropathy. Am. J. Nephrol. 2014, 40:64-74. 46. Ruggenenti P, Porrini EL, Gaspari F, Motterlini N, Cannata A, Carrara F, Cella C, Ferrari S, Stucchi N, Parvanova A et al.: Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Diabetes Care 2012, 35:2061-2068. 47. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B: Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med. 2016, 375:323-334. This randomized placebo-controlled trial showed that treatment with the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes mellitus at high cardiovascular risk significantly decreased the composite end-point of doubling of serum creatinine; development of estimated GFR<45 ml/ min/1.73 m2, development of macroalbuminuria, initiation of renal replacement therapy, or death from renal disease. 48. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ et al.: Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 2015, 373:2117-2128. 49. Johnsson KM, Ptaszynska A, Schmitz B, Sugg J, Parikh SJ, List JF: Urinary tract infections in patients with diabetes treated with dapagliflozin. J. Diabetes Complications 2013, 27:473-478. 50. Johnsson KM, Ptaszynska A, Schmitz B, Sugg J, Parikh SJ, List JF: Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J. Diabetes Complications 2013, 27:479-484. 51. Nicolle LE, Capuano G, Fung A, Usiskin K: Urinary tract infection in randomized phase III studies of canagliflozin, a sodium glucose co-transporter 2 inhibitor. Postgrad. Med. 2014, 126:717. 52. Nyirjesy P, Sobel JD, Fung A, Mayer C, Capuano G, Ways K, Usiskin K: Genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. Curr. Med. Res. Opin. 2014, 30:1109-1119.
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ScienceDirect ACE and SGLT2 inhibitors: the future for non-diabetic and diabetic proteinuric renal disease Norberto Perico1, Piero Ruggenenti1,2 and Giuseppe Remuzzi1,2,3 Most chronic nephropathies progress relentlessly to end-stage kidney disease. Research in animals and humans has helped our understanding of the mechanisms of chronic kidney disease progression. Current therapeutic strategies to prevent or revert renal disease progression focus on reduction of urinary protein excretion and blood pressure control. Blockade of the renin-angiotensin system (RAS) with angiotensinconverting enzyme inhibitors and/or angiotensin II type 1 receptor blockers is the most effective treatment to achieve these purposes in non-diabetic and diabetic proteinuric renal diseases. For those individuals in which nephroprotection by RAS blockade is only partial, sodium–glucose linked cotransporter-2 (SGLT2) inhibitors could be a promising new class of drugs to provide further renoprotective benefit when added on to RAS blockers. Addresses 1 IRCCS—Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo & Cele Dacco`, Bergamo, Italy 2 Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy 3 Department of Biomedical and Clinical Sciences “L. Sacco”, University of Milan, Milan, Italy
to be 1.2 million, a 32% increase from 2005, with deaths from diabetic and hypertensive kidney disease comprising over 75% of these deaths [2]. The prevalence of endstage kidney disease (ESKD) patients worldwide receiving renal replacement therapy (RRT) with maintenance dialysis has also increased 1.7 times from 165 patients per million population (pmp) in 1990 to 284 pmp in 2010 [3]. ESKD is only the tip of the iceberg. While the prevalence of CKD remains ill-defined, especially in low- and middle-income countries [4], it is estimated that more than 322 million individuals are currently affected by CKD worldwide [5]. With a population that is ageing, steep increases in the incidence of type 2 diabetes mellitus and hypertension globally are driving the growth in CKD burden, putting an enormous burden on health care resources [1]. Kidney disease is therefore a global public health priority. Given the very high individual and societal cost of RRT with dialysis or transplantation, efforts to prevent or halt renal disease progression are of utmost importance to reduce the clinical and economic consequences of CKD.
Progressive nature of chronic kidney disease Corresponding author: Remuzzi, Giuseppe ([email protected])
Current Opinion in Pharmacology 2017, 33:34–40 This review comes from a themed issue on Cardiovascular and renal Edited by David A Taylor, Robert J Theobald, Abdel A Abdel-Rahman and Ethan J Anderson
http://dx.doi.org/10.1016/j.coph.2017.03.006 1471-4892/ã 2017 Elsevier Ltd. All rights reserved.
Chronic kidney disease: a global health problem Chronic kidney disease (CKD) is a key determinant of poor health outcomes for major non-communicable diseases, and has a risk-multiplier effect on cardiovascular diseases (CVD) [1]. Recent findings from the Global Burden of Disease studies have highlighted CKD as an important cause of global mortality [2]. In 2015, the number of reported deaths due to CKD was estimated Current Opinion in Pharmacology 2017, 33:34–40
Most chronic nephropathies progress relentlessly to ESKD. Research in animals and humans has helped our understanding of the mechanism of CKD progression. These studies have established that most renal diseases progress to renal failure as a consequence of functional adaptations intervening in the kidney, after the original disease process causes an initial loss of nephron units [6]. Such changes, extensively studied in rodents, include glomerular hyperperfusion, and hypertension of the remaining nephrons, which begin with enhancing the filtration capacity of single nephrons. These changes initially minimize the functional consequences of nephron loss but eventually become detrimental, contributing to the impairment of the glomerular barrier’s size selective properties and inducing protein ultrafiltration. An excess of protein contents in Bowman’s space and in the lumen of tubules ultimately results in the activation of inflammatory and apoptotic pathways, fuelling progressive renal damage [6]. As shown by in-vitro and in-vivo studies, the activation of a variety of cytokines, growth factors and vasoactive substances may result in abnormal accumulation in the mesangium and in the tubulo-interstitium of extracellular matrix collagen, fibronectin and other components that are responsible for glomerulosclerosis and interstitial fibrosis and progressive renal injury [6] (Figure 1). www.sciencedirect.com
ACE and SGLT2 inhibitors: the future for non-diabetic and diabetic proteinuric renal disease Perico, Ruggenenti and Remuzzi 35
Figure 1
Degenerative/inflammatory glomerular diseases
Interstitium Proximal tubular cell
Nephron loss
ET-1 MCP-1 mRNA Fractalkine RANTES
Lymphocyte/macrophage infiltration
Compensatory glomerular capillary hypertension pore dimension
ET-1 MCP-1 Fractalkine RANTES
DNA
Nuclear signals for gene transcription
Cytokines/ chemokines Interstitial fibroblasts
Proteinuria
Excessive tubular protein reabsorption
Cell proliferation
ECM ECM protein degradation synthesis
Tubular interstitial damage and inflammation DISEASE PROGRESSION Current Opinion in Pharmacology
Mechanisms of progression of proteinuric kidney disease. A reduction in the number of nephrons as a consequence of various glomerular diseases results in compensatory glomerular hemodynamic changes that are ultimately detrimental. In particular, by mechanical stretching, the increased glomerular capillary pressure directly injures glomerular cells. Glomerular hypertension also impairs the glomerular capillary size-selective function which causes excessive protein ultrafiltration, and, eventually, podocyte injury and proteinuria. The intraglomerular capillary hemodynamic changes are mainly driven by increased synthesis of angiotensin II. Protein overload of proximal tubular cells as a consequence of increased glomerular permeability to proteins activates intracellular signals that promote cell apoptosis or cause increased production of inflammatory and vasoactive mediators and of growth factors. These substances are released into the interstitium, inducing progressive inflammation and injury. ECM, extracellular matrix; ET-1, endothelin-1; MCP-1, monocyte chemoattractant protein-1; RANTES, regulated upon activation, normal T cell expressed and secreted.
Renin-angiotensin system blockade for renoprotection in non-diabetic nephropathies Current strategies to prevent or revert renal disease progression focus on reduction of protein trafficking along with strict blood pressure control. Blockade of the renin-angiotensin system (RAS) by means of angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin II type 1 receptor blockers (ARBs) is the most effective treatment to achieve these purposes. Animal models of proteinuric chronic nephropathy have clearly documented that RAS inhibitors reduce intraglomerular hydraulic pressure and improve the selectivity of the glomerular barrier, an effect that translates into a reduction of proteinuria and prevention of glomerulosclerosis [7]. Similar effects have been reported on the clinical ground. In patients www.sciencedirect.com
with non-diabetic proteinuric nephropathies, the Ramipril Efficacy In Nephropathy (REIN) trial showed that, at equivalent blood pressure control, the ACEi ramipril halved the rate of glomerular filtration rate (GFR) decline, providing evidence for a nephroprotective effect of protein trafficking reduction [8]. Renoprotection was time dependent, and in patients on continued ramipril therapy for at least 5 years, the rate of GFR decline progressively improved up to 1 ml/min/1.73 m2 per year, approximating the physiological age-related loss of GFR with time in individuals with no evidence of renal disease [9]. There is also indirect evidence that in humans regression of CKD is achievable with ACEi therapy [10]. In ten of the REIN’s study patients on ACEi, there was a break point indicating the transition from an initial phase of Current Opinion in Pharmacology 2017, 33:34–40
36 Cardiovascular and renal
progressive GFR decline to a second phase of gradual renal function improvement, possibly reflecting regression of renal lesions along with some degree of renal tissue regeneration [11]. The beneficial effect of the ACEi on GFR was paralleled by further proteinuria reduction across the break point [11]. Subsequent experimental studies in rat models have documented that amelioration of renal function achieved by chronic ACEi therapy was mediated through regression of sclerosis in most partially injured glomeruli and regeneration of renal vasculature [12,13].
ACEi or ARBs for renoprotection in diabetic kidney disease In the past two decades studies have also demonstrated the renoprotective effect of RAS blockade in patients with type 2 diabetes and nephropathy. The Reduction of Endpoints in non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial [14] and the Irbesartan in Diabetic Nephropathy Trial (IDNT) [15] showed that ARB treatment, as compared to placebo, reduced the incidence of a composite endpoint of doubling of serum creatinine concentrations, ESKD, or death by 16% and 19%, respectively, in two large cohorts of patients with type 2 diabetes and overt nephropathy. Renoprotection was associated with a significant reduction in urinary protein excretion. Independent of treatment allocation, both trials showed that an early reduction in urinary protein excretion was associated with slower renal function loss and reduced cardiovascular mortality in long-term [16]. Experimental and clinical studies have also pointed out the importance of early pharmacologic intervention in type 2 diabetic kidney diseases (DKD) to afford better renoprotection. In a rat model of streptozocin-induced diabetes, ACE inhibition provided remarkable renoprotection against the development of nephropathy, but only when treatment was started early in the course of the disease [17]. In the IRbesartan MicroAlbuminuria type 2 diabetes in hypertensive patients (IRMA-2) trial, a fulldose irbesartan therapy reduced the 2-year incidence of progression to macroalbuminuria from 14.9% to 5.2% compared to placebo and increased the rate of regression to normoalbuminuria [18]. RAS inhibition is renoprotective even when treatment is started earlier, as shown in the Bergamo Nephrologic Diabetes Complication Trial (BENEDICT) in type 2 diabetic patients with hypertension and normal urinary protein excretion rate [19]. Four years treatment with the ACEi trandolapril reduced the risk of progression to microalbuminuria from 10.9 to 5.8% compared to nonACEi therapy [19]. Interestingly, among normoalbuminuric patients, any measurable albuminuria bore significant cardiovascular risk and in those receiving ACEi therapy, the event rate was uniformly low [20]. Current Opinion in Pharmacology 2017, 33:34–40
All the above findings have been recently confirmed in a study that, modeling DKD progression in large cohorts of type 2 diabetic patients, documented a superior beneficial effect of RAS intervention in the early stages of the disease in delaying ESKD than later treatment [21].
Dual RAS blockade for renoprotection Combination therapy with ACEi and ARBs inhibits the RAS more efficiently than does each agent alone through an additive effect. Consistently, the results of a metaanalysis indicated that dual RAS blockade was associated with greater proteinuria reduction compared to ACEi or ARB monotherapy in patients with non-diabetic chronic nephropathy [22]. Concerns, however, have been raised about double RAS inhibition since combined treatment of ramipril and telmisartan increased the risk of the prespecified composite end point of any dialysis, serum creatinine doubling or death compared with either drug alone in a large study comprising 25 620 patients with atherosclerotic disease and/or diabetes with end organ damage [23]. However, the excess of adverse renal outcomes on combination therapy was largely driven by the more frequent need for short-term dialysis, conceivably a treatment-related acute effect on renal hemodynamics that is reversible upon treatment withdrawal, rather than an indication of CKD progression. Moreover, 96% of patients in this study had normo- or micro-albuminuria, pointing to limited kidney damage to halt or reverse. Debate about the role of dual agent RAS blockade in the management of CKD has recently been reignited by the results of a meta-analysis showing that ACEi and ARB combination therapy is the most effective approach to prevent ESKD in patients with DKD [24]. This treatment benefit was independent of blood pressure control, but was associated with great improvement in albuminuria [24]. The above findings can be taken to suggest that dual RAS inhibition could be a powerful tool to slow or prevent the progression of chronic proteinuric nephropathies, provided that treatment is accompanied by close monitoring of renal function and serum electrolytes, adjusting drug doses accordingly.
The need of novel treatments for renoprotection in DKD A significant cohort of patients treated with RAS blockers, however, shows only partial anti-proteinuric response, eventually heralding a progressive loss of renal function in most cases. To address this shortcoming, we have designed a response driven, individually tailored approach to these proteinuric CKD patients, the Remission Clinic program [10]. It is a multimodal intervention protocol targeting urinary proteins by dual RAS inhibition with ACEi and ARBs up-titrated to maximum tolerated doses, by intensified blood pressure control, amelioration of dyslipidemia with statins, smoking cessation, lowering salt intake and healthy lifestyle implementation in patients who have overt proteinuria despite ACEi therapy www.sciencedirect.com
ACE and SGLT2 inhibitors: the future for non-diabetic and diabetic proteinuric renal disease Perico, Ruggenenti and Remuzzi 37
[25,26]. Although largely effective in non-diabetic proteinuric nephropathies, in approximately two-thirds of type 2 diabetic patients with overt nephropathy, remission of proteinuria was not achieved through the Remission Clinic approach, and the renal risk remained elevated. These patients urgently need novel therapeutic interventions that would complement the effects of RAS blockade in order to improve clinical outcomes [27,28].
Sodium–glucose Co-transporter 2 inhibitors in DKD Novel treatment strategies for DKD are on the horizon but investigating their efficacy is still in infancy. Beside treatment with Vitamin D receptor activators [29] or selective endothelin receptor antagonists [30,31], the most attractive approach based on the current risk/benefit results is the use of selective inhibitors of the sodium– glucose cotransporter 2 (SGLT2). Increased glucose in glomerular ultrafiltrate, as it occurs in diabetes, leads to augmented glucose delivery to the proximal tubule where it is reabsorbed along with sodium largely (80–90%) by
SGLT2 and for the remaining by SGLT1 cotransporters [32,33,34]. Accordingly, selective inhibition of SGLT2, leads to substantial glycosuria, lowering blood glucose and facilitating weight loss in individuals with diabetes [32,33,34]. Apart from the ability to increase urinary glucose excretion and eventually helping to control glycemia, SGLT2 inhibitors have recently raised substantial interest for additional properties potentially relevant for renoprotection in DKD. This possibility rests on the observation that in diabetes as it occurs in normal physiologic settings, SGLT2 and SGLT1 at proximal tubule co-transport sodium (Na+) with glucose, so that Na+ delivery to the macula densa at the juxtaglomerular apparatus will diminish [33,34]. These effects reduce the tubuloglomerular feedback signal by promoting the local release of renin and angiotensin associated with inhibition of adenosine production that result in the constriction of the nearby glomerular efferent arteriole and dilation of the adjacent afferent arteriole. Thereby intraglomerular hemodynamic changes occur leading to increase in intraglomerular capillary pressure and single-nephron
Figure 2
Diabetes
Diabetes and SGLT2 inhibition SNGFR
SNGFR AA vasodilation
AA vasoconstriction
SGLT2
SGLT2
JGA
JGA
SGLT1
SGLT1 Glucose and Na reabsorption
EA vasoconstriction
Glucose and Na reabsorption
Na delivery to JGA
EA unaffected
Na delivery to JGA
Glucose excretion
Glucose excretion Current Opinion in Pharmacology
Effect of diabetes and SLGT2 inhibition on single nephron glomerular filtration rate and Na excretion. In diabetic patients with poor glycemic control, the increased glucose in the glomerular ultrafiltrate leads to augmented glucose delivery to the proximal tubule. Here glucose tubular reabsorption, along with Na+, is increased by both SGLT2 and SGLT1. Thus, Na+ delivery to macula densa (juxtaglomerular apparatus) will be diminished, eventually reducing tubuloglomerular signals (afferent arteriole vasodilation, efferent arteriole vasoconstriction), thereby increasing single nephron glomerular filtration (SNGFR). In this setting, inhibition of sodium–glucose linked cotransporter-2 (SGLT2), by reducing glucose/Na+ reabsorption in the proximal tubule, increases Na+ delivery to the macula densa, leading to afferent arteriole vasoconstriction, while leaving unaffected efferent arteriole vascular tone. Intraglomerular capillary pressure decreases, and SNGFR returns to normal. AA, afferent arteriole; EA, efferent arteriole; SGLT2 and SGLT1, sodium–glucose linked costransporter-2 and 1, respectively; JGA, juxtaglomerular apparatus; SNGFR, single nephron glomerular filtration rate.
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38 Cardiovascular and renal
glomerular filtration rate (SNGFR) [33,34,35] (Figure 2). On the other hand, inhibition of SGLT2 reduces sodium reabsorption in the proximal tubule, enhances Na+ delivery to the macula densa, eventually activating the tubuloglomerular feedback and lowering SNGFR [33,34,35] (Figure 2). Attenuation of glomerular hyperfiltration would translate in prevention of long-term glomerular damage contributing to reduce the progression of DKD. A growing body of evidence in animals with experimental diabetes has indeed suggested that SGLT2 inhibition affords renal protection. These studies have shown that SGLT2 inhibitors, empagliflozin and dapagliflozin, ameliorated diabetic nephropathy by attenuating albuminuria, mesangial expansion and interstitial fibrosis via combined effects on glomerular hemodynamics and inhibition of renal inflammation and oxidative stress mostly secondary to improvement of glycemia [36–38]. These in vivo findings confirmed previous in vitro evidence that SGLT2 inhibitors attenuated inflammatory and fibrotic responses of proximal tubular epithelial cells exposed to high glucose [39]. Of note, very recently, in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, the administration of dapaglifozin ameliorated the RAS activation characteristic of this model of type 2 diabetes by down regulation of the renal expression of the angiotensin II type 2 receptor (AT1R), which may have further contributed to the renoprotective effect of this new class of drugs in these animals [40]. Clinical studies focused on renal protection in DKD are limited. Nevertheless, the existing data in type 2 diabetic patients and stages 1-3 CKD reported that SGLT2 inhibition with empagliflozin, canagliflozin, or dapagliflozin was associated with initial acute reduction in GFR, followed by GFR stabilization on the long-term [41,42,43,44]. The acute decline in GFR was reversible after drug discontinuation, suggesting that SGLT2 inhibitors are capable to ameliorate glomerular hyperfiltration [41,44,45], a major determinant of renal disease progression in diabetes [46]. In parallel with their beneficial effect on renal hemodynamics, SGLT2 inhibitors reduced albuminuria during the 24 to 52 weeks of follow-up [41,43], anticipating possible renoprotection in longer term. Indeed, the EMPA-REG study in 7020 patients with type 2 diabetes at high cardiovascular risk, has recently shown that over a median follow-up of 3.1 years empagliflozin therapy significantly slowed the progression of kidney disease and reduced the rate of clinically relevant renal events, such as doubling of serum creatinine or ESKD compared to placebo when added to standard care [47]. These results, however, have been part of the prespecified secondary objective of the EMPA-REG trial, aimed primarily to cardiovascular outcomes [48]. So far dedicated renal protection studies such as the large Current Opinion in Pharmacology 2017, 33:34–40
randomized double-blind placebo-controlled CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical EvalNCT02065791) are underway, and are uation expected to provide more insight into the renoprotective efficacy of SGLT2 inhibitors. The main shortcoming of this new class of drugs is the risk of developing mild to moderate genitourinary infections that, however, are manageable [49–52].
Conclusion In the past decades, experimental and clinical studies have clearly documented that RAS blockers are the first line treatment to limit disease progression and renal function decline in patients with proteinuric non-diabetic and diabetic nephropathies. For those individuals in which nephroprotection by RAS blockade is only partial, SGLT2 inhibitors could be a promising new class of drugs to provide further renoprotective benefit. To this respect, trials in type 2 diabetic patients using a combination of SGLT2 with ACEi or/and ARBs should be encouraged. Furthermore, given that, beyond diabetes, SGLT2 inhibition also affects renal hemodynamic, proteinuria, blood pressure, the combination of this new class of drugs with RAS blockers may also potentially provide benefit in proteinuric non-diabetic CKD. More important, however, it would be to have therapeutic interventions with combination treatment in both diabetic and non-diabetic setting started in the early stages of the disease, when more beneficial effect in delaying ESKD than later treatment is expected [21].
Conflict of interest statement Nothing declared.
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