Hello everyone, I'm dr. Katherine Tuttle, executive director for research at Providence Healthcare and professor of medicine at the University of Washington. Today I'll discuss GLP-1 receptor agonists in the clinical management of CKD and diabetes. These are my disclosures.

Our goals today will be to discuss the GLP-1 receptor agonists for cardiovascular risk reduction and for preservation of kidney function in CKD. Then to comprehend team care as a strategy to implement personalized therapies for heart and kidney protection.

The KDIGO guidelines have recently been updated. They will soon be published as a 2022 version for diabetes and CKD. Here we see the treatment paradigm that's recommended. We now recommend that an SGLT2 inhibitor, with or without metformin, be used as first-line therapy in these individuals. But note that the next therapy in line is a GLP-1 receptor agonist if needed to achieve an individualized glycemic target or if a person has persistent albuminuria despite these therapies.

The story of the GLP-1 receptor agonists and kidney disease really started with the cardiovascular outcome trials in type 2 diabetes. They were very successful with regard to reducing major cardiovascular events. Particularly atherosclerosis CVD events such as myocardial infarction, stroke and even cardiovascular death with at least two agents in the class, liraglutide in LEADER and semaglutide in PIONEER 6. However, the major secondary outcomes were related to kidney disease. Across the class, these were shown to reduce macro albuminuria and slow GFR decline from early to late stage CKD.

In this meta-analysis of the CV outcome trials, we see the kidney disease outcomes. Overall, you can see that the risk reduction was about 21 percent with a hazard ratio of 0.79, highly statistically significant. When we look at the outcome without albuminuria it just misses statistical significance with a hazard ratio of 0.86. And a p-value of 0.089. But I'd like to point out that in the cardiovascular trials people were selected for cardiovascular disease and mostly had normal kidney function. So the earliest indicator would be albuminuria in most cases. So it'll be easier to show a treatment effect

on the short-term outcome of albuminuria.

With regard to what happens in patients with advanced CKD we turned to AWARD-7. This was a glycemic lowering study comparing two doses of dulaglutide versus insulin glargine in people with type 2 diabetes and moderate to severe CKD. In contrast to the CV outcome trials, these patients had low GFR entry, note baseline of 35. And in the insulin treated group, represented by green, we see study GFR decline over one year. Where it is stabilized with either dose of dulaglutide. In the right panel you see the bar graphs just showing the GFR change at 26 and 52 weeks. With a large reduction, as we would expect in this high-risk group with insulin. We don't see this effect with either dose of dulaglutide.

This has now been verified in a slope analysis, that was done post hoc of semaglutide in PIONEER 6 and SUSTAIN 6. If you look at the middle bars, the group with GFR between 30 and 60 this is where we see the biggest difference. With semaglutide slowing GFR decline in a difference between the treatment groups of 1.07 ml per minute, per 1.73 meters squared per year. And to put this in perspective for you; the CKD prognosis consortium has shown that an estimated treatment difference of just 0.75 in GFR is highly predictive of a benefit of the treatment on an outcome related to kidney disease. Such as kidney failure or substantial GFR decline.

In another analysis, presented here at the ERA we show the effect on the KDIGO risk categories in patients treated with semaglutide versus placebo in SUSTAIN 6 Red represents moving to a higher risk category. You can see that in all of the patients, who are eligible to move to a higher risk category so low, moderate and high risk, fewer patients treated with semaglutide developed a higher risk state during treatment. Conversely, if we look at the green bars at the bottom those eligible to move to a lower risk state were more likely to do so with semaglutide and less likely to do so with placebo. Both albuminuria and GFR contributed to the improvement in this outcome.

When we go back to AWARD 7, this is an exploratory, but pre-specified analysis looking at substantial GFR decline defined by 40 percent or greater, or end stage kidney disease requiring dialysis or transplant. Because this was a high risk population, even in a one-year study we had a number of events, over 60 events. You can see there was more than a 50% reduction with the highest dose dulaglutide compared to insulin. The subset with macroalbuminuria, about half of the cohort these are the highest risk patients to progress. You see that the patients treated with high-dose dulaglutide, the blue line on the right, had a substantially reduced risk with a hazard ratio of 0.25, 75 percent risk reduction.

With regard to the biological plausibility, this has been extensively reviewed here in this Nature Reviews Nephrology paper from our group. But we really think that these agents are largely acting in an anti-inflammatory manner. Just to remind you that in the diabetic kidney, there are immune cells in the glomerulus. There's a profound infiltrate of T-lymphocytes, macrophages, other immune cells and myofibroblast of the tubular interstitium. In preclinical models we see that treatment with a GLP-1 receptor agonist largely abrogates this inflammatory response and restores kidney structure, both in the glomerulus and the tubular interstitium toward normal.

There are GLP-1 receptors in the kidney. In some intrinsic cells, such as endothelial cells and variably in proximal tubular cells depending on the model. But what may be very important are the infiltrating inflammatory cells particularly macrophages and T-lymphocytes, which carry GLP-1 receptors. When a GLP-1 receptor is activated by one of our GLP-1 receptor agonists it actually activates processes of anti-inflammatory, including inhibiting NF-kB. This promotes expression of pro-inflammatory and pro fibrotic mediators, inhibition of apoptotic signaling and a reduction in production of reactive oxygen species by inhibiting heme oxygenase 1. So all this is to say, this is not serendipity and their strong biological plausibility of why the kidney would be protected in clinical studies.

That said, what do we know about use of these agents in clinical practice? This is data from the U.S. from something called the Optimum Health Care database. It's an insurance database of people who have commercial insurance. And if you look at the use of GLP-1 receptor agonists, in the orange line, and also SGLT2 inhibitors, in the yellow line, over time juxtaposed against the major trials that drove use of these agents. You can see that the uptake is still very low. As recently as 2020 some fifteen percent of patients with diabetes and CKD were getting a GLP-1 receptor agonist. So we have a long way to go to implement these therapies so patients may benefit.

And to that end we really reimagine that team care is going to be required because of the enormous number of patients and the increase in complexity of medical management. And we really also know that it's going to take a team to manage all of the different dimensions and numbers of patients. So we're really emphasising the importance of harmonising our guidelines so KDIGO is now harmonised with the American Diabetes Association, American Heart Association guidelines. We are really emphasising the importance of not only multiple specialties but particularly pharmacist that will help us with medication management, so that we can get the job done for patients, who stand to benefit.

A patient who might stand to benefit is illustrated in this case here. This is a 42 year old man, with type 2 diabetes diagnosed in youth at age 15. And he was referred to the nephrologist because of CKD, but he also has obesity, hypertension and dyslipidemia. And he's on a classic regiment of an ACE inhibitor, calcium channel blocker, statin, metformin, and insulin glargine. But when we see him, we know that his blood pressure is 142 over 94, his BMI is 40, has no volume retention. Potassium is okay at 4.8, but it's GFR is just 23 with a serum creatinine at 3.3 and he has macro albuminuria about 1400 milligram per gram and A1C is high at 8.2. And his LDL cholesterols is 94 and he hasn't had an event, but a chest CT showed incidental coronary calcification. So this is a classic patient with type 2 diabetes and CKD who also has a phenotype of atherosclerotic CVD and obesity.

So the question regarding this patient is: How could glucose-lowering agents be adjusted to optimize his care? Do you want to stop the insulin glargine and metformin and start a GLP-1 receptor agonist? Or do you want to increase his insulin by 50%? Or possibly add glimepiride? Or maybe do both B and C? What we decided to do was stop the insulin glargine metformin and started GLP-1 receptor agonist much as we did in the AWARD 7 trial.

And in fact besides, the glucose lowering effects and the kidney protective effects. it is very important to recognize that these agents again are highly protective and particularly against ASCVD and cardiovascular death. Note that in this meta-analysis of all the trials, even in the patients with low GFR, below 60, they benefited as much, as least as much as patients with higher GFR. So importantly we will also protect his heart, which is a major risk for this individual who had clearly has evidence of coronary heart disease and multiple risk factors.

So what other strategies might we use to optimize his care? Do you want to intensify antihypertensive therapy to a lower blood pressure goal for example, less than 130 over 80 and maybe even lower. Do you want to add aspirin and intensify his statin therapy? What about counseling about physical activity, nutrition, and weight? Or do you want to do all of the above?

Well, really the correct answer is we should be doing all of these things because as KDIGO points out the fundamental foundation of good care of people with diabetes and CKD is good risk factor management overall and then specific anti hyperglycemic therapies to lower glucose and protect the heart and kidney.

So the take home points are that both SGLT2 inhibitors and GLP-1 receptor agonist along with our conventional ACE inhibitors or ARBs are now recommended therapies for persons with diabetes and CKD. And multidisciplinary team care, particularly including the CKD risk assessment and monitoring, will help promote implementation of personalized therapies to optimize heart and kidney protection.

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