Ladies and gentlemen, dear colleagues, it's my pleasure now to give an introductory talk on new insights and guidelines: What are the challenges for CKD and diabetes? And I will actually focus on the guidelines. And the next slide before I go into my talk show my dualities of interest. So my conflicts.

And then I will move into the topic itself. There are in my opinion, three gigantic risks that center on patients with diabetic kidney disease. Namely premature death, kidney failure, and cardiovascular disease. And the question for us as physicians treating patients with diabetic kidney disease or diabetes and CKD. What helps?

And there is a list of medications. Insulin was tested in the ORIGIN trial against non-insulin-based treatments in type 2 diabetes, and it was not of help. 14,000 patients, six years. No difference between treatment. There is now data from the CAROLINA study published about two or three years ago on sulfonylureas. Again, no difference to the comparator DPP-4 inhibitors in this case and we have quite a large database. Also on CKD patients with type 2 diabetes from the CARMELINA study in which DPP-4 inhibitors showed no benefit on the above three gigantic risks compared to placebo. So, a good database on the one hand of a number of treatments that provide no harms, but also no benefits, despite important impact on metabolic risk. How about the SGLT2 inhibitors and the GLP-1 receptor agonist? We have dedicated outcome trials in those with diabetes and CKD with SGLT2 inhibitors, the CREDENCE trial and the DAPA-CKD trial and the two trials show that on the three gigantic risk. Those trials, not only lower, let's say blood glucose. Those drugs, also lower the risks that I outlined above. Similarly, GLP-1 receptor agonists also lower that risk. Whether they do it in a dedicated population with CKD and diabetes, is explored currently in our FLOW trial. And I hope that many of you contribute to that trial that is fully randomized and will report in about 2 years from now.

How did the guidelines implement the findings from those large outcome trials on a large number of anti-diabetic drugs? That is shown here from the recent KDIGO guideline on the treatment of type 2 diabetes with CKD and that guideline shows change in gears actually because it says, when you treat with the drug in patients with type 2 diabetes and CKD, do not use metformin alone. Do always use metformin with an SGLT2 inhibitor. That said there are limits for using metformin, primarily based on GFR there are also limits on using SGLT2 inhibitors also based on GFR, also based on side effects. And the guideline also says, when you need another glucose lowering drug, do not use any of the others but use GLP-1 receptor agonist because of known benefits and because of superiority over placebo, which is not shown by the other drugs listed here. So it's an important drug or class of drug for us, as nephrologists treating patients with diabetes and kidney disease.

Why that emphasis on GLP-1 receptor agonist. Well, the KDIGO guideline with stems from 2020, it's now being overworked, but not published yet, but that from 2020, shows this slide that in the LEADER trial, SUSTAIN trial, REWIND trial, all these trials showed a benefit on the cardiovascular outcomes with the GLP-1 receptor agonists, and also showed benefits on kidney outcomes with the GLP-1 receptor agonists and I will go into some more detail particularly on the kidney

benefits of those drugs. As I said, those data are limited to 2020, actually 2019, the guideline was issued in 2020.

Why the emphasis also on kidney outcomes? And why is that not yet complete? Lacking the FLOW trial. LEADER and SUSTAIN 6 were trials in a general population of patients with type 2 diabetes and cardiovascular risk, but not based on renal risk, but there were a lot of patients in those two trials with a kidney risk. On the left hand side, the LEADER data, on the right hand side the SUSTAIN data. and the kidney outcome was defined by microalbuminuria, Coming up, doubling of serum creatinine, end-stage kidney disease or renal death. So there is a stepwise increase because only when the patients came to their visit, serum creatinine was measured or urine albumin was measured in the two trials and for that combined or composite outcome huge benefit for the active drug. Risk reduction in the range of, let's say a plus minus 30%. And which was driven in the two trials, actually by the reduction in microalbuminuria, new microalbuminuria, but also effects on eGFR, as shown on the next slide.

That's a bit of a busy slide. It shows the data for SUSTAIN 6 and PIONEER. So for semaglutide. The blue bars are the patients treated with active drug, with semaglutide, and placebo in the brown bars on the left hand side. All patients in this trials, right hand side, subdivided by baseline eGFR low, and baseline eGFR normal. And on the ordinate you see, the decrease in eGFR over the duration of the trials. Clearly with the active drug, there was particularly huge effect on the decline in eGFR in those treated with the active drug, as compared to placebo. Less but still an effect also visible in the overall population.

There is a recent trial and would like to end on this trial. in which an exendin-like drug was used, again a GLP-1 receptor agonist. And there was some discussion of whether the exendin-based drugs are also effective or not. This was tested by Hertzel Gerstein in the AMPLITUDE-O study. And I again show the kidney outcomes. The trial was highly effective also on cardiovascular outcomes. This is the the kidney outcomes on the right hand side, placebo group blue, red, the actively treated group. And as with SUSTAIN, PIONEER and LEADER and REWIND, you see a clear benefit of the active drug on the kidney outcome. On the left hand side of the slide, I have alluded to the fact that also, the typical kidney outcome that we are looking at in kidney outcome trials, end-stage kidney disease or eGFR loss of 40% of more was less frequent, definitely less frequent with the active drug than with placebo. 76 versus 121 events, new microalbuminuria as in all the other trials, also less frequent.

So we look into the future to see the FLOW trial and the question comes up. What's impact of SGTL2 inhibitors? So far SGLT2 inhibitors for the trial durations that I showed before, were only very infrequently used in patients with CKD and diabetes. Now AMPLITUDE-O which was the latest incoming trial, had a sizable number of patients that were on SGLT2 inhibitors when randomized. On the left hand side you see the kidney outcome placebo versus active drug. So the exendin-based drug. The clear difference on the kidney outcome, on the right hand side, in patients that were using SGLT2 inhibitors at baseline also a large benefit. So we can conclude from this trial and actually also from other trials, based on the subgroups, it looks as if the combination of SGLT2 inhibitors with GLP-1 receptor agonist on kidney outcomes will be additive. And one will not be inhibiting let's say the benefits of the other and that's good news for the future and I'm happy that my colleagues will further explore these data for the benefits of all patients in the next two talks. Thanks a lot.

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