As blogged previously, we have strong evidence that the SGLT2 inhibitors (SGLT2i’s) provide powerful kidney protection in people with chronic kidney disease (CKD) and type 2 diabetes (T2DM), and we also have evidence from the DAPA-CKD trial that the SGLT2 inhibitor dapagliflozin provides similar kidney protection in people with chronic kidney disease, who do NOT have type 2 diabetes.  Health Canada has now formally approved dapagliflozin (Forxiga) to reduce the risk of sustained GFR decline, end stage kidney disease, and cardiovascular and renal death in adults with chronic kidney disease, with or without type 2 diabetes.


We already have the SGLT2i canagliflozin (Invokana) indicated in Canada for people with T2DM and CKD to reduce the risk of end stage kidney disease, doubling of serum creatinine, and cardiovascular (CV) death (canagliflozin has not been studied in people without T2DM).  Empagliflozin (Jardiance) is currently under study in people with CKD, with or without T2DM and with or without proteinuria.  Across the CV outcome trials of this class of medications, people with CKD were found to have renoprotective benefits, as well as heart failure (HF) and CV protective effects.


The new Health Canada indication for dapagliflozin is based on the DAPA-CKD Trial.  As blogged previously, this study was designed to evaluate the efficacy of  dapagliflozin (DAPA) at a dose of 10mg daily, on renal and cardiovascular outcomes in adult patients with CKD. Specifically, patients were included if they had an eGFR of 25-75 mL/min/1.73m2 and urine albumin:creatinine ratio (UACR) 22.6-565 mg/mmol (200-5000mg/g), and were on stable treatment with an ACEi/ARB for ≥4 weeks before screening. The trial enrolled a total of 4304 participants, including 1398 (32.5%) without T2DM. The mean eGFR was 43.1mL/min/1.73m2, and the median UACR was 108mg/mmol (949mg/g).

The primary endpoint of the trial was a composite of the time to the first occurrence of any of the following components of the composite endpoint: a sustained ≥50% decline in eGFR, end-stage kidney disease (ESKD), or renal or CV death. When compared to placebo, after a median follow up of 2.4 years, there was a statistically significant 39% relative risk reduction (RRR) in this composite endpoint for the DAPA group, with a number needed to treat (NNT) of just 19 to prevent one event.



SO: How do we use SGLT2 inhibitors in clinical practice, in people with chronic kidney disease?

Dr Louise Moist, nephrologist and Professor of Medicine and Epidemiology, University of Western Ontario, London, Canada, and I (the diabetes doc) are taking on some commonly asked clinical questions today!


1. Does dapagliflozin work equally well in people with vs without T2DM?

Dr Moist:  Dapagliflozin is currently the only SGLT2i for which we have a completed renal outcome study including people without T2DM.  Remarkably, the effect of dapagliflozin on the primary outcome was consistent across all prespecified subgroups.  Participants with or without T2DM had similar benefits, with a 36% and 50% reduction in risk,  respectively. Similar findings were seen for the secondary outcomes: kidney-specific composite outcome [sustained ≥50% decline in eGFR, ESKD, or renal death (43% vs 49% risk reduction)];  all-cause mortality (26% vs 48% risk reduction); and CV death or hospital admission for heart failure (HF) (30% vs 21% risk reduction).

The proportions of participants in the dapagliflozin and placebo who had serious adverse events or discontinued study drug due to adverse events did not vary between those with and those without type 2 diabetes.


2.  Does dapagliflozin work equally well across different levels of eGFR or levels of proteinuria?

Dr Moist: DAPA-CKD enrolled participants with an eGFR of 25-75 mL/min/1.73m2 and UACR 22.6-565 mg/mmol. The effect was similar across eGFR levels when they compared those with eGFR ≤ vs > 45mg/min.  The effect was also similar when comparing those with UACR ≤ 113  mg/mmol  vs > 113 mg/mmol.

The effect of dapagliflozin on the primary outcome was also consistent among patients with diabetic nephropathy (n=2510; HR 0·63, 95% CI 0·51-0·78), glomerulonephritides (n=695; HR 0·43, 0·26-0·71), ischaemic or hypertensive CKD (n=687; HR 0·75, 0·44-1·26), and CKD of other or unknown cause (n=412; HR 0·58, 0·29-1·19;), with similar consistency seen across the secondary outcomes.


3.  How often should I check GFR and electrolytes after starting an SGLT2i?

Dr Moist: There are no guidelines as to when to monitor the eGFR after initiation. We do know from all the SGLT2i studies that the eGFR decreases approximately 4-5 ml/min/m2 after initiation.  In my opinion, in stable patients, the eGFR can be checked within 2-3 months of initiation. In patients with more advanced CKD or with multiple comorbidities you may consider checking sooner.


4.  Are the potential side effects of SGLT2i any different in patients with CKD with T2DM vs without T2DM?

DrSue:  Three published outcome trials have included patients without type 2 diabetes (the DAPA-CKD trial, the EMPEROR-REDUCED HFrEF trial, and the DAPA-HF HFrEF trial).  In these trials, people with or without type 2 diabetes had a similarly increased risk of volume depletion, as well as a similarly slightly increased risk of genital yeast infection.  People without type 2 diabetes do not have a risk of hypoglycemia with SGLT2i, nor do they have a risk of diabetic ketoacidosis.  It is important to ensure that patients are aware to stay well hydrated when taking SGLT2 inhibitors. In my clinical experience, genitourinary hygiene measures such as using cleansing wipes like ‘Tucks’ after urination can help prevent yeast infections.



5.  In what types of CKD should I NOT initiate an SGTL2i?

Dr Moist: DAPA CKD excluded participants with polycystic kidney disease (PCKD), type 1 diabetes, lupus nephritis, ANCA-associated vasculitis, or patients who had received immunotherapy for primary or secondary kidney disease within 6 months before enrolment.

However, dapagliflozin is now indicated for a significant proportion of patients with CKD, as the types of CKD that were included in DAPA CKD make up approximately 80% of patients with CKD (diabetic nephropathy, chronic glomerulonephritides, ischaemic or hypertensive chronic kidney disease, or chronic kidney disease of other or unknown cause).

Note that patients with PCKD were excluded because they lose the ability to concentrate urine and are greater risk of dehydration. Patients with lithium induced interstitial nephritis, and patients at risk of dehydration ( eg high output ostomies), should be monitored more frequently if initiated on an SGLT2i.



6. If my patient with CKD is on diuretic treatment, should I adjust this when starting SGLT2i? 

Dr Moist: The management of the diuretic depends on the patient’s volume status and the indication for the diuretic. The SGLT2i’s have a BP lowering effect (2-4 mmHg) and a diuretic effect, which may be greater if the glucose levels are high. In my clinical experience, there is minimal diuretic effect in people who have a lower eGFR, and/or who don’t have T2DM. If the patient is normotensive and euvolemic without HF, you can consider reducing the diuretic, or stopping if it’s low dose. I generally do not make any changes to the diuretic in patients with a history of HF, unless specifically indicated by the clinical status.


BOTTOM LINE:  The SGLT2 inhibitors started out as treatments for type 2 diabetes, and are now becoming established as treatments for heart failure and for kidney disease, even in people without type 2 diabetes.  Dapagliflozin is now indicated in Canada to protect kidneys in people with chronic kidney disease, with or without type 2 diabetes – a welcome improvement to the treatment armamentarium of CKD patients.


Disclosure: The information and opinions expressed in this newsletter are those of the authors. Creation of the newsletter was supported by honoraria provided by AstraZeneca, the makers of dapagliflozin.


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