What is relevant for nephrology with regard to GLP-1RA in CVD?

Hello, my name is Filip Knop. Today I'm here to talk about the evolving science with GLP-1 receptor agonist in chronic kidney disease with a particular focus on what is relevant for nephrology.

Let me start out by introducing you to glucagon-like peptide 1, or in short GLP-1. GLP-1 is one of two incretin hormones being secreted from the small intestinal tract. The other one being glucose-dependent insulinotropic polypeptide, GIP, secreted from the upper part of the gastrointestinal tract.

GIP has never really been exploited therapeutically, because in early days we saw no insulinotropic effect of GIP in patients with type 2 diabetes and also, at least in mice, actually caused obesity. So that was why GIP was put to the grave in therapeutical sense. Nowadays, we have tirzepatide, a dual GIP-GLP-1 receptor agonist, that might change this in the future. But now back to GLP-1, which basically has been a shooting star in therapeutical terms. And one of the reasons that GLP-1 receptor agonists have been so successful therapeutically is because of the many cardiovascular outcome trials that have been made in the type 2 diabetes field.

And in this slide you see a meta-analysis made by Michael Nauck that was presented last year at the EASD meeting virtually. You can see that in this meta-analysis of GLP-1 receptor agonists, cardiovascular outcome trials clearly show that GLP-1 receptor agonist improves the risk of cardiovascular disease in patients with type 2 diabetes. And importantly, you can also see that hospitalization for heart failure, and also the risk of kidney-related outcomes, they are also significantly reduced by GLP-1 receptor agonist therapy.

So today I would like to go into the mechanisms behind these beneficial effects of GLP-1 receptor agonists on both cardiovascular disease but also chronic kidney disease. So I think there is a general notion that there is no single mechanism that causes these beneficial effects. It's probably multifactorial mechanisms contributing to the beneficial effects of GLP-1 receptor agonist treatment. Here I have listed some of them. Let's take a look at them individually.

Glycaemia. It's well known that GLP-1 receptor agonists improve glycemic levels in patients with type 2 diabetes and pre-diabetes. And one of the reasons is that GLP-1 receptors are found on the islet beta cells, secreting insulin. This is an old experiment performed by Michael Nauck in Germany showing that a GLP-1 infusion in patients with type 2 diabetes, as compared to a placebo infusion, pretty much can normalize the hyperglycemia over a four hour infusion period. And the mechanisms behind this are an increased insulin secretion combined with a suppressed glucagon infusion. But the really interesting part of this experiment was what happened in the end of the experiment when plasma glucose levels normalized. There you can see that, upon normalization of plasma glucose, the insulinotropic effect and also the glucagonal steady effect simply ceases. Meaning that the glucose-lowering effect of GLP-1 receptor agonist therapy is very safe in terms of the risk of hypoglycemia. You simply don't see hypoglycemia when treating patients with type 2 diabetes with GLP-1 receptor agonist therapy.

It's also well-known and well-described that GLP-1 receptor agonist therapy causes body weight loss. The reason for that is that GLP-1 receptor agonists stimulate GLP-1 receptors in the brain. In this slide you see GLP-1 receptors throughout the mouse brain, and these GLP-1 receptors are particularly localized to portions of the brain where appetite is regulated. Here you can see that when you infuse a labelled GLP-1 receptor agonist, injected in the periphery of mice, it actually is able to find its way into the brain sticking to the GLP-1 receptors up there. And when these GLP-1 receptors are activated they cause neural activation in appetite controlling centers. So, the cause of the body weight loss with GLP-1 receptor agonist therapy is because of these GLP-1 receptors being activated, translating into reduced food intake.

And here you see some clinical results from the STEP program investigating the effect of the GLP-1 receptor agonist semaglutide in obese subjects and you can see some pretty robust body weight lowering effects indicated by the blue bars, as compared to placebo, the grey bars, now up to 18 percent weight loss in an obese population. Pretty impressive, if you ask me.

Moving on to the blood pressure lowering effect of GLP-1 receptor agonist therapy. This is a slide showing different head-to-head trials comparing different GLP-1 receptor agonists and showing the effect of systolic blood pressure. And you can see, overall, there are some pretty nice, but also perhaps rather small, effects on systolic blood pressure. But the good thing here is that they all tend to go in the same direction with a systolic blood pressure reduction of around 4 millimeters of mercury.

What are the mechanisms about this blood pressure lowering effect of GLP-1? We know that GLP-1 receptors are present in the kidney. They are positioned in the afferent arteriole in the juxtaglomerular apparatus and when these are stimulated, they vasodilate the afferent arteriole and that may contribute to the blood pressure lowering effect of GLP-1 receptor agonists. GLP-1 also suppresses the sodium-hydrogen 3 exchanger that may contribute to a degree of natriuresis.

And let me show you some results from one of my colleagues in Denmark, Ali Asmar, who investigated the effect of a GLP-1 infusion in healthy subjects being volume expanded with sodium chloride. And here you see a clear effect of GLP-1 on natriuresis and the urinary sodium excretion when GLP-1 is infused as compared to placebo. He didn't see any effect on renal hemodynamics measured by chromium EDTA clearance.

Also, he measured some natriuretic peptide but he didn't see any effect of GLP-1 on ANP or BNP, as clearly showed here. Neither, he saw effects on renin or aldosterone in these subjects, but he did see a suppressive effect of GLP-1 on angiotensin II levels. So, perhaps, that may also be important for the blood pressure lowering effect of GLP-1.

Moving on to blood lipids. When we use GLP-1 receptor agonist therapy in patients with type 2 diabetes, there is a small, and perhaps it's not very clinically relevant, but nevertheless, there is a small change in total cholesterol levels in the fasting state and they tend to decrease which can be considered beneficial in that population.

But perhaps more importantly, treatment with GLP-1 receptor agonists therapy, in both, type 2 diabetes, and in this case obese individuals, also reduces postprandial levels of important lipids such as triglycerides and apolipoprotein B48, which may also contribute to the beneficial effect in terms of cardiovascular disease risk reduction, and perhaps also chronic kidney disease risk reduction.

There may also be other potential mechanisms, and one important one is the anti-inflammatory effect of GLP-1. Here you clearly see a dose-dependent anti-inflammatory effect of the GLP-1 receptor agonist semaglutide from the PIONEER studies. The higher the dose, the greater the reduction in CRP in these studies. So you may say that this is because you also see a reduction in body weight with a higher dose compared to the lower dose, but in the PIONEER 2 study comparing the SGLT2 inhibitor empagliflozin with oral semaglutide we see a particular decrease in the CRP levels, only with oral semaglutide and not with empagliflozin, despite the fact that the two treatments actually decrease body weight to the same extent.

So, now let's move back to some of the big cardiovascular outcome trials with secondary outcomes investigating renal effects. Here, you see two large cardiovascular outcome trials investigating liraglutide in the LEADER study and semaglutide in SUSTAIN 6. And you see the results in terms of the composite renal endpoint here, which is a composite endpoint, a hard renal endpoint. And in both studies, there was a clear and significant reduction in this renal endpoint. The same was true for the REWIND study investigating dulaglutide. So clearly some beneficial effects in terms of renal endpoints here.

These are the individual composite endpoints from the overall renal endpoint in the LEADER study, and what is clear here is that the reduction in the renal endpoints is driven by a reduction in new onset or persistent microalbuminuria, whereas the other parts of these composite endpoints did not change in the LEADER study.

But some ongoing studies will help us to understand how the GLP-1 receptor agonist reduces renal events even better. We have four studies, evaluating more than 30,000 patients with semaglutide. And in these studies, there are some nice renal endpoints.

First of all, we have the FLOW study which is the first dedicated renal endpoint study with GLP-1 receptor agonist therapy. In this study, more than 3,500 subjects with type 2 diabetes and a certain degree of chronic kidney disease will be randomized to once weekly semaglutide or placebo with the co-primary endpoint to persistent 50% reduction of eGFR, persistent eGFR of less than 15, or chronic or renal replacement therapy, renal death or combined with cardiovascular death, or plus minus cardiovascular death. So these patients, they are either high risk or very high risk of chronic kidney disease events, so, hopefully, this trial will show the benefits of GLP-1 receptor agonists in these patients.

Then we have the two large cardiovascular outcome trials, SOUL and SELECT, investigating the cardiovascular disease risk of GLP-1 receptor, or semaglutide, the old version in SOUL and the injectable version in SELECT, in patients with type 2 diabetes in SOUL and obese, non-diabetic patients in SELECT. Primary outcome is MACE, but a predefined secondary outcome is this combined renal event. So, clearly these studies will also help us understand whether the GLP-1 receptor agonist has benefits in chronic kidney disease patients.

Then we have the REMODEL study, which will focus on the mode of action of semaglutide in patients with type 2 diabetes and chronic kidney disease. In this study, patients with type 2 diabetes and chronic kidney disease, with a moderate to very high risk of renal events, will be included. The key endpoints originate from a number of different investigations, ranging from functional MRI scans, measured eGFR, albumin-creatinine ratio, and also the investigators want to take kidney biopsies in order to investigate the effect of GLP-1 on different expression analysis in the kidney tissues.

So I think in the future, we will be much wiser with regard to both the effects of GLP-1 receptor agonist therapy in patient with CKD and also the mode of actions. So with that, thank you very much for your attention.