Summary | Addressing the remaining questions on SGLT2 and CKD: a review of new outcome trials
Prof. Baigent reviewed ongoing SGLT2 outcome trials in CKD patients, set up to address the question whether SGLT2 inhibitors have any value for patients with established CKD.
Prof. Wanner already discussed the promising results of the EMPA-REG OUTCOME trial on the effects of empagliflozin in patients with a mild degree of renal impairment. The key question that needs to be answered is whether there is any impact of empagliflozin on the rate of progression from CKD to end-stage renal disease in patients with more severe CKD than those included in the EMPA-REG OUTCOME trial, before the drug may be more widely used in patients with CKD.
The starting point to consider a broader application, is the observation that, as eGFR declines, glycosuria is also lower , which has in turn an impact on HbA1c levels. Indeed, a pooled analysis of phase 3 trials with empagliflozin showed a difference in HbA1c levels of 0.9% in patients with well-preserved eGFR >90 ml/min/1.73m2 compared with placebo, whereas a much smaller impact was observed in patients with eGFR <30 ml/min/1.73m2. In contrast, the time to doubling of creatinine levels, initiation renal replacement therapy or renal death in EMPA-REG outcome was only slightly influenced by baseline levels of renal function . Prof. Baigent: ‘Thus, a reduction in CKD outcomes did not depend on renal function. There is a sort of uncoupling of the effects of the drug on glycemic parameters and its apparent effects on renal outcomes. This encourages us to think that we might be able to achieve a benefit even among patients with much more severe renal disease’.
Another question is how empagliflozin affects individuals without diabetes, who make up about 60% of all CKD patients depending on geographical region. Prof. Baigent: ‘It would be great to find a drug that prevents CVD and prevents progression to end-stage renal disease in non-diabetic CKD patients. Since the SGLT2 protein is also present in non-diabetic patients and it functions in exactly the same way, SGLT2 inhibition might work in non-diabetic CKD patients’.
It has already been shown that empagliflozin has hemodynamic effects in overweight people, with an 8% reduced eGFR after treatment . Similarly, reduced creatinine levels were found in pre-diabetic or obese people after treatment with empagliflozin . ‘These data suggest that the effects of SGLT2 inhibition may be relevant to the very large number of CKD patients without diabetes’.
Before translating data from the EMPA-REG OUTCOME trial and CANVAS program to clinical use of the drugs in CKD patients, there are some key areas of uncertainty that need to be addressed . About the efficacy, Baigent wondered: ‘What happens to the effects of SGLT2 inhibition as eGFR declines and what will happen to the end-stage renal disease outcomes?’ Beneficial effects on HF were observed, but the effect of the drugs on CV outcomes as eGFR decreases remain to be elucidated. Similarly, the effects of empagliflozin on CV and renal outcomes in patients without diabetes are unknown. About safety, prof. Baigent said: ‘We would like to know the magnitude of known adverse effects as eGFR declines?’ Naturally, it needs to be studied whether there are any unanticipated adverse effects in patients with severe renal impairment.
Next, Prof. Baigent summarized currently ongoing trials. First, the Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial recruited 4401 T2DM patients >30 years old (mean age: 63 years) with HbA1c levels between 6.5 and 12% (mean: 8.3%), eGFR 30-90 ml/min/1.73m2 (mean 56: mL/min/1.73m2), UACR between 300-5000 (median: 927), on a RAS blocker at baseline. Patients were randomized to either empagliflozin 100 mg daily or placebo. The primary endpoint is doubling of serum creatinine, end stage kidney disease, or death from CV or renal causes .
Secondly, the Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (DAPA CKD) is currently recruiting about 4000 patients aged >18 year, eGFR 25-75 ml/min/1.73m2, UACR between 200-5000, on RAS blockade at baseline. Patients are randomized to either 5 or 10 mg dapagliflozin or placebo. The primary endpoint is a 50% decline in eGFR, end stage renal disease, or death from renal or CV causes .
Prof. Baigent described the third study in more detail. The EMPA-KIDNEY study is about to start, and will recruit patients >18 years old who are at risk for progression to end stage renal disease and who are on stable RAS blockade at baseline. A key element is that treatment with SGLT2 inhibitors is not part of standard care. There will be two groups of patients; the first group will have eGFR of 20-45 ml/min/1.73m2, with or without proteinuria, and is considered very likely to progress to end stage renal disease. This group is anticipated to potentially benefit from SGLT2 inhibition. The second group of patients will have eGFR between 45-90 ml/min/1.73m2, UACR of >200 mg/g or a protein creatinine ratio greater than 300 mg/g. Study enrollment will consist of a screening visit, followed by a run-in period with placebo of 8 to 12 weeks in order to identify people who are not likely to comply with their treatment long term, and also to ensure that they are on the appropriate RAS blockade. Eligible patients will then be randomized to either 10 mg empagliflozin or placebo and will be followed every six months for a fixed period until the beginning of June 2022 .
Prof. Baigent compared the three trials by discussing the inclusion criteria, primary endpoints and power, and secondary endpoints. The three studies have slightly different age criteria and a key difference is that the CREDENCE study only includes patients with T2DM, whereas the DAPA CKD study and the EMPA-KIDNEY study also include patients without diabetes. Another criterion that differs slightly is renal function, since the EMPA-KIDNEY study includes patients with an eGFR of 20-45 ml/min/1.73m2, irrespective of albuminuria, while the other two studies only include patients with an eGFR of ≥30 and <90 ml/min/1.73m2 (CREDENCE) and 25-75 ml/min/1.73m2 (DAPA-CKD).
A total of over 2000 primary endpoints is anticipated in these three studies. A substantial number of patients with CKD can quite reasonably and reliably demonstrate whether SGLT2 inhibition has an impact on the vascular and renal endpoints. The statistical assumptions are very similar for all three trials and each trial is well powered to detect an effect of around 20% in the primary composite renal outcome.
The three studies have slightly different secondary outcomes, but in essence all of the studies try to understand the impact of SGLT2 inhibitors on or renal outcomes. Prof. Baigent: ‘By the time these three trials have finished, it should be possible to determine to some extent how the effects of these drugs vary according to baseline levels of renal function, whether or not patients have diabetes, and according to other key parameters that vary among the different types of patients who are managed in renal programs’.
Prof. Baigent finished with the conclusion: ‘By 2022 we will likely have data on the effects of SGLT2 inhibition on about 13,500 patients with CKD. And that will include about 3,000 patients without diabetes. We should have around 2000 primary outcomes and while it is a composite renal outcome, there should be substantial numbers, some hundreds of end stage kidney disease outcomes. Despite this, there will be limited power for subgroups, and so we do need to make sure that, if any new SGLT2 inhibitors come along, we have data on patients with CKD. That would potentially need new trials. This drug class is very interesting, and I think it has the potential to cause major advances in the management of patients with CKD.’
This is a summary of the presentation given by prof. Baigent, during the PACE symposium entitled 'Diabetic Kidney Disease: Exploring mechanisms and outcomes of SGLT2 inhibition', held during ERA-EDTA in Copenhagen, Denmark, on May 25, 2018