I have no experience in using SGLT-2 in non diabetic patients. In few transpalnted patients who were administered SGLt-2 inhibitors, there was an initial increase in serum creatinine which is expected and reported. Recommendations take into consideration the cost at the national or global level. in my opinion the drugs of choice for diabetes would be GLP-1 RA, SGLT-2 inhibitors and Metformin, if the person is obese i would use GLP-1 RA if the patient can afford it, with or without SGLT-2 inhibitors,
Dear Dr Mohsin thank you for your contribution. We don’t have any experience in using SGLT-2 inhibitors in non-diabetic CKD patients as well, as these drugs have not been officially approved for this group of patients yet. However, our experience from diabetic patients is that there is an initial increase in serum creatinine and a functional reduction in eGFR as this drug category promotes afferent arteriole vasoconstriction through tubuloglomerular feedback and by a direct ability to decrease glomerular hyperfitration. These actions , along with their anti-proteinuric, anti-inflammatory, anti-fibrotic and antioxidants effects could probably explain the long term nephroprotection. Consensus reports from ADA/EASD, EURECA-m and DIABESITY recommend SGLT-2 inhibitors as 2nd line treatment for type 2 DM with established atherosclerotic CVD and/or CKD. But the main open question is what about proteinuric non-diabetic CKD patients? Are these drugs so effective in this group of patients as well so that longterm nephroprotection and cardioprotection will justify their use and high cost?
Although the use of SGLT-2 in patients with diabetic nephropathy seems quite promising and has various benefits in everyday clinical practise, what about the urinary side-effects? According to your opinion how can we monitor for urinary tract infections and should we be causious in diabetics with neurogenic bladder?
Dear Stefanos you are right indeed. Urogenital side effects are the most common with SGLT-2 inhibitors. Genital mycotic infections were significantly increased in diabetics using SGLT-2 inhibitors vs placebo but side effects were mild to moderate, resolved with topical antifungal treatment and no drug discontinuation was required. Severe urinary tract infections did not appear to increase significantly in the big clinical trails (i.e EMPAREG OUTCOME). Regarding symptoms of neurogenic bladder , there are some recent studies that did not show worsening of such symptoms with SGLT-2 inhibitors.
The risk of increased likelihood of urinary tract infections with SGLT-2 inhibition is related to glycosuria induced by these drugs in patients with type 2 DM. These drugs in published studies rarely induced hypoglycemia. I suppose that if used in CKD patients without type 2 DM (so with a good glycemic control) SGLT-2 should not cause the loss with urine of great amounts of glucose as in 2 DM. The risk of urinary tract infections for this reason could be reduced. Have you some information regarding this topic?
Dear Dr Coppolino I completely agree with your opinion . This is the idea.. but we don’t have any information yet. Time will tell…
This is a very Important Topic! MANY studies, testing the effects of SGLT-2 inhibitors in non Diabetic CKD have been started. Please see also the phase 2 DIAMOND study: NCT03190694. The main reason why these studies have been planned is that SGLT-2 inhibitors reduce the intraglomerular hypertension, a mechanism that is shared by almost ALL kidney disease (often as a compensatory mechanism). In my opinion, onther than in patients with impaired eGFR, it will be important to use test these drugs in non-DM CKD patients with proteinuria ( > 150 mg/d ). Do you think they may work also in absence of proteinuria?
Dear Dr Provenzano thank you for your pointed comment. When you say “in the absence of proteinuria” which patient group do you have in mind? If you mean patients with non-proteinuric CKD, we know that hyperfiltration and proteinuria create a viscious circle and having this in mind we can’t tell if SGLT-2 inhibitors work in the absence of proteinuria. Until now, all trials have included diabetics or non-diabetics with proteinuric CKD. So first, hopefully we are going to see positive results from the ongoing trials in non-DM proteinuric CKD and then if they work, we might test them in non-proteinuric patients. The suggested pleiotropic effects of SGLT-2 drugs could support the hypothesis of nephroprotection and cardioprotection in non-proteinuric CKD…
With regard to the cardiovascular benefits of SGLT-2 inhibitors, especially improved heart failure outcomes, the three major trials of SGLT-2 inhibitors included either diabetic patients with established cardiovascular disease or diabetic patients considered at high risk for cardiovascular disease according to the presence of additional risk factors. I would like to know your opinion whether the pathophysiological mechanisms via which SGLT-2 inhibitors provide cardioprotection will persist and be significant in nondiabetic patients with proteinuric CKD?
Dear Ani thank you for your pointed comment! It is well known that the burden of heart failure is high in CKD, with left ventricular hypertrophy being the most typical structural abnormality. Both albuminuria and eGFR are both predictors of heart failure in CKD, as recently shown from the CRIC study. Moreover, the suggested pathophysiological mechanism of SGLT-2 in terms of cardioprotection which might be at least partly dissociated from the mechanism of nephroprotection includes antihypertensive effects, diuretic effect with increased free water clearance, improved energetic utilization, reduction of glomerular hyperfiltration, anti-inflammatory and anti-oxidative and possibly other effects not yet elucidated, It is probable that we will see improved cardiovascular outcomes in nondiabetic patients with proteinuric CKD. It should be noted that there are no specifically defined cardiovascular inclusion criteria in the two ongoing studies of SGLT-2 inhibitors in proteinuric CKD (as compared to the three major studies of SGLT-2 inhibitors in diabetic patients with or without CKD). However the magnitude of the effects remains to be established in this patient group.
Another important beneficial effect of SGLT-2 inhibitors in CKD patients could be the ability to decrease uric acid levels. Indeed, depending on the magnitude of such effect, the use of uric acid-lowering agents could be reduced or avoided and this could be relevant especially if we consider that, for example, allopurinol may rise safety concerns. What do you think about this? Do you know if targeted trials have been designed to evaluate if this pleiotropic effect of SGLT-2 inhibitors may be beneficial to CKD patients in the long term?
Dear Dr Cernano, indeed trials of SGLT-2 inhibitors as well as a relatively recent metanalysis have shown that SGLT-2 inhibitors reduce serum levels of Uric Acid. Nevertheless, although hyperuricemia has been suggested as a potential risk factor for CKD progression, the benefit of uric acid lowering therapies in terms of nephroprotection remains controversial. On the other hand, evaluation of the effect of these agents on reducing serum Uric Acid levels may as well be an additional end-point (easy to estimate) in any trial of SGLT-2 inhibitors.
I fully agree with you all, this pleiotropic effect of SLGT-2I can really expand their range of action!
Very interesting and a topic with remarkably evolving data. I share similar thoughts with other participants on this dialogue reagrding the outcome of SGLT-2 inhibitors administration in non-diabetic, proteinuric, hypertensive or not patients who lack the upregulation of SGLT-2 cotrasporters that chronic hyperglycemia induces. Natriuresis in this group of patients is only partly mediated by SGLT-2 cotrasporters considering that in normally functioning tubules (i.e. normoglycemia) SGLT-2 are responsible for less than 5% of sodium reabsorption. In your opinion are we anywhere near comparing directly SGLT2i with traditional natiuretic agents?
Dear Vivi thank you for sharing your thoughts with us. SGLT-2 inhibitors through their primary mechanism of action cause osmotic diuresis. Nevertheless, considering that the site of action is the proximal tubule and knowing the escape mechansisms of the nephron, we don’t expect them to be as potent diuretics as the traditional diuretic agents we currently use. So, in my opinion there is not obvious need for direct comparison between them. We already know that SGLT-2 are upregulated in diabetics but we can’t be sure if this upregulation exists in proteinuric non-dibetic patients, probably not. Moreover, according to current evidence, the measured inhibition achived by SGLT-2 inhibitors is less than 50% based on urine glucose excretion. So, we hopefully “put our money” on the pleiotropic effects of these agents…
Much promising data are coming to the surface that could change the management of diabetic CKD patients. By proxy, I would like to ask if there are any studies that report improvement in allograft function or reduction of proteinuria in renal transplant recipients. Could SGLT-2is increase time to chronic allograft nephropathy? These drugs seem to be theoretically safe, as far as interactions with immunosuppressants are concerned (https://doi.org/10.1016/j.trre.2016.09.001), but given the higher impact and prevalence of UTI in RTR, can we safely prescribe SGLT-2is in these patients?
Dear Andronikos, thank you for your comment!!! Until now there are scarce data in the literature regarding use of SGLT-2 inhibitors in renal transplant recipients (RTRs). Actually, I manage to find only two relatively small studies of SGLT-2 inhibitors in RTRs with NODAT have shown promising results regarding safety and efficacy of these agents in NODAT (DOI: 10.2337/dc19-0093 AND 10.1111/ajt.15223). Thus, these agents may be a reasonable choice as add-on therapy in NODAT (considering eGFR levels are appropriate according to the general indications/contraindications of these agents). However, it would be to daring to assume nephroprotective properties of these agents in RTRs with proteinuria and chronic allograft nephropathy, considering the complex pathophysiologic mechanisms involved in chronic allograft nephropathy (both immune and non-immune mechanisms involved). Regarding UTIs in RTRs, the above studies did not show an increased incidence of UTIs in patients using SGLT2 inhibitors and additionally the major studies of SGLT2 inhibitors in diabetic patients showed a significantly increased incidence of mycotic genital infections but not significant UTI. Nevertheless, we need larger studies so as to have a more clear picture regarding benefits and complications of SGLT2 inhibitors in RTRs with NODAT.
It is quite interesting that beside glycaemic and blood pressure control, SGLT2 inhibitor therapy seem to have direct renoprotective effects that may explain the results obtained in non-diabetic models of CKD. Recent data suggest potential mechanisms for the renoprotective effects of these medications such as improvement of podocyte damage, reduction of oxidative stress and inflammation in the kidney. Further data is needed to confirm these pleiotropic effects, as well as to explain how and in which specific non-diabetic CKD the SGLT2 inhibitors could be beneficial.
Dear George, I completely agree with your comment. We are looking forward for the results of the ongoing studies in non-diabetic proteinuric CKD patients but I am afraid that it will take some time until we have the resutls available and we can give an evidence based answer to this question. Unitl, then we can only make assumptions and “bet on it”…
Thank you for sharing with us these very interesting findings. Ι would like to raise some concerns over the potential renoprotective benefits of SGLT-2s based on the fact that there is a relatively small percentage of patients with eGFR<60 and proteinuric diabetic nephropathy in the current literature. For example, in the EMPA-REG OUTCOME study, 1819 patients had eGFR<60 and only 19% of them had macroalbuminuria which seems to be suggestive of heterogeneity of primary disease and therefore diversity of outcomes. My opinion is that studying a more uniform population could probably help us to better clarify the efficacy and safety of SGLT-2 inhibitors in diabetic nephropathy and then move on to the non-diabetics? I would love to hear your opinion about this.
Let me note the data from the secondary analysis of the CANVAS program (Neuen et al, Circulation 2018), where it was shown that the effects of canagliflozin on cardiovascular and renal outcomes were not modified by baseline level of kidney function in people with type 2 diabetes and a history or high risk of cardiovascular disease down to eGFR levels of 30 mL/min/1.73 m2. In addition the reduction in risk of major adverse cardiovascular events, hospitalization for heart failure, and progression of kidney disease appeared similar across different levels of kidney function down to eGFR 30 mL/min/1.73 m2. For sure, as you ve already mentioned, further investigation is needed.
There are several recent studies that show the beneficial effect of SGLT- inh on MACE. This is why FDA approved empagliflozin for reducing CV death in adults with type 2 diabetes. This class of agents causes afferent arteriolar vasoconstriction by manipulating tubulo-glomerular feedback, thereby reducing intraglomerular pressure via mechanism that is parallel and complementary to those of RAS blockade. That’s why a reductive impact upon albuminuria is expected. Indeed, it is a very interesting topic. Further studies in non diabetic patients are needed to ensure the necessity of prescribing SGLT-2 inh to non diabetic proteinuric patients.
Impressive Data Shown at the International Society of Nephrology 2019 World Congress of Nephrology. Results from the phase 3 CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) Canagliflozin Cuts Risk of Renal Failure, Death 30% in Patients With Type 2 Diabetes and CKD