Prof David Wheeler (University College London, London, UK), co-chief investigator of the DAPA-CKD study joined Dr Harriette Van Spall (McMaster University, Hamilton, CA) to discuss the results of the study.
I’m dr harriet vance ball cardiologist and associate professor of medicine from mcmaster university in canada and i am delighted to have with me professor david wheeler the co-principal investigator of the dapa ckd trial a landmark trial presented at the esc meeting this week welcome professor wheeler thank you dr van spell it’s my pleasure to be here so you
Co-led this trial with dr hurstbank who presented the results a couple of days ago why don’t you tell us about the inclusion criteria and the methodology of this trial now of course um i’d be delighted to do that so we we took dapogiflozin which is of course a drug designed to treat diabetes and we had a pretty good idea when we started the trial that this
Drug would improve outcomes in in patients with type 2 diabetes and chronic kidney disease um but we also had the thought that the drug might help patients who had chronic kidney disease that wasn’t due to diabetes so we recruited patients both with and without diabetes into the dapa ckd trial they all had chronic kidney disease they all had albuminuria but
Around about a third of them actually didn’t have type 2 diabetes as a comorbidity right so eligible patients were randomized in a one-to-one fashion to either dapogliflozin 10 milligrams a day or to placebo on a background of ace and arb therapy would you like to tell us about your child population and their characteristics yes so aces and arbs are our standard
Care in this population so we wanted um as many patients as possible to be on aces and arbs um we recruited patients who had certain biomarkers of kidney disease so gfrs between 25 and 75 and high levels of albuminuria so we recruited a group of patients who had effectively established chronic kidney disease based on egfr criteria and albuminuria criteria and
And the vast majority of them were on aces and arbs those that had diabetes needed to have reasonably well controlled diabetes right important to note uh in terms of implementation of the study results that you excluded patients with type 1 diabetes and those with some inherited conditions such as polycystic kidney disease lupus nephritis and anky vasculitis
Yeah so we we decided that there were kidney diseases that were unlikely to be impacted by by this drug because of the very nature of the underlying kidney disease um so we actually excluded patients with a genetic condition autosomal dominant polycystic kidney disease with cysts grow in the kidneys we didn’t think the drug would reverse cyst growth and also
Patients who had active immune mediated kidney disease who were on immunosuppression so lupus for example and we excluded patients with with type one diabetes um i think largely because we we were concerned about safety issues um with the drug in patients with type 1 diabetes particularly diabetic ketoacidosis which has been a problem in entire modern diabetics
Treated with these compounds right and they’ve been routinely excluded from trials of svlt2 inhibitors you also excluded those with severe heart failure and those who were in the post-mi setting or had been recently revascularized and i bring that up because we’re cardiologists and so these are important facts to note for our cardiology viewers yeah but only
Recent mis so so we patients with it with a history of myocardial infarction going back you know a few months were were allowed in but patients who were just recovering from an mi weren’t allowed in heart failure is difficult in in kidney disease because when the kidneys don’t work well the patients get fluid overloaded and and you know may get diagnosed as
Having heart failure um but we didn’t want to include patients who were you know breathless and um severely um their physical activity was severely impaired by by their heart failure so we didn’t include the higher new york classes of heart failure right so you had about 4 300 patients in your trial population and after a mean duration of follow-up of about
Two and a half years you had some remarkable effects noted in your primary endpoint why don’t you tell us how you went about selecting the primary endpoint and what your findings were so the primary endpoint was a composite which was largely a renal composite so it included things that matter to patients with with kidney disease dialysis the need for a kidney
Transplant reaching what we call end-stage kidney disease um a gfr um below 50 ml per minute but also declines in in gfr so that we could pick up those patients who had um early deterioration in their kidney function during the trial um we had uh um uh what we called renal death in the end point which meant death due to untreated end-stage kidney disease
And we put cardiovascular death in the end point as well um so the the primary was a composite of renal endpoints with cardiovascular death right and what were your findings well the trial was actually stopped early um by the data safety monitoring board which surprised us a little bit and the data safety monitoring board informed the steering committee that
They’d stopped the trial dues the overwhelming efficacy of the drug so that was quite exciting um we therefore closed the trial down um we ensured that all the patients came up for their final study visits and and then um in in july of this year we were able to unblind and look at the data um i think based on what we knew already as i said that was we thought
There was a good chance that patients with diabetes may benefit from this intervention in terms of that primary composite endpoint um but i think what uh what we were really pleased to see was that the patients who’d been recruited without diabetes also benefited um from the intervention uh and and on top of that we saw a mortality benefit as well so when we
Looked at all-cause mortality which was one of our pre-specified secondary endpoints um we saw a reduction in in all cause mortality uh in in the in this patient population and that’s that’s important because this is the first trial that we’re aware of that’s shown a reduction in all-cause mortality in in a group of patients with chronic kidney disease right
Remarkable findings so the um hazard ratio for the primary endpoint the primary composite renal endpoint which also included death from cardiovascular causes was 0.61 with a relatively small confidence interval so a good amount of precision and as you say the benefits apply to those without diabetes which is also remarkable and which is congruent with the
Findings of dapa hf which was presented last year of course and all of the secondary endpoints also were reduced with this intervention so what are your thoughts on the implications and how one might go about implementing this drug certainly there has been some inertia and the uptake of sgl t2s in those with chronic kidney disease despite a past trial that
Assessed the efficacy of an sglt2 i believe that was the credence trial so what do you think the implications are and how might implementation efforts be more successful in applying these findings to our patients so look some really good questions um credence looked at a group of patients with diabetes and they all had diabetes and chronic kidney disease
Um and also read out positively so um there was a similar combined renal uh composite endpoint that included cardiovascular death as well and the results of that study you know were released in april 2019 it took a good year for the licensing to change and i think we are now beginning to see uh changes in the therapeutic approach that we’re taking to these
Patients but we should remember that these are diabetes drugs and and kidney doctors may be initially a little bit reluctant to treat patients who don’t have diabetes with diabetes drugs so i think um we’re going to have to do um a lot of education among health care professionals share our results reassure people about the safety because the safety profile
Of the drug was was good during the study um and uh slowly start to to change people or health care professionals prescribing habits and also perhaps uh you know work with patients to uh to understand um you know why uh they they would want this drug and what would help them um in terms of their interactions with the healthcare professionals right you did
Mention safety endpoints and so we should probably add there was no diabetic ketoacidosis seen in the intervention group which i found quite remarkable because there was some uh that was noted in the placebo group yep why don’t you talk about the safety endpoints and what the findings are yeah so we saw you know the expected um side effects with this drug um
In fact we were only we we pre-selected the safety point safety endpoints that we were going to look at and and we were particularly concerned about diabetic ketoacidosis and hypoglycemia um we actually saw no ketoacidosis or hypoglycemia in the um in in the patients who didn’t have diabetes who went into the trial so that was hugely reassuring um there was
No excess of amputations that’s been a concern um with drugs in this class from previous studies and we so we saw no unexpected safety signals that we hadn’t predicted even in the patients who didn’t have type 2 diabetes going into the study so i think we were reassured by the safety data that came out of the trial right so congratulations on a well-conducted
Trial which has a great um implications on patients with chronic kidney disease that can offer our patients with chronic disease improvements and multiple endpoints that include renal endpoints cardiovascular endpoints and importantly all-cause mortality how are you going to celebrate the end of this trial it’s it’s a sort of a different environment now in the
Virtual meeting space it’s not quite the same as presenting to a large audience and uh celebrating with your colleagues and co-investigators what are you doing as a team to celebrate yeah it’s uh it’s interesting i mean we you know it’s very efficient doing virtual meetings and you can get a large number of people um a lot of our emails have carried sort of
Images of champagne glasses and and crackers and stars and celebration but but we’ve missed the opportunity to celebrate and and i think what we’re going to do is stall the celebration for a few months until we can meet face to face and then we’ll we’ll have the party then wonderful i thank you so much for joining me today it was my pleasure and an honor to
Meet you and i wish you well in your ongoing research and celebrations thank you delighted to talk to you thank you very much
Transcribed from video
ESC 2020 Discussion: The DAPA-CKD Study — Prof David Wheeler & Dr Harriette Van Spall By Radcliffe