Renal Benefits of SGLT2s and GLP1s

This transcript has been edited for clarity.

Jay H. Shubrook, DO: Hi. I'm Jay Shubrook, a family physician and diabetologist at Touro University in California. Today, we're going to talk about what to do with our patients who have diabetes and chronic kidney disease (CKD).

I'm delighted to have with me Dr Katherine Tuttle, who is a professor of medicine at the University of Washington. She is uniquely qualified to talk about this topic, as she is both an endocrinologist and a nephrologist, and she is on the board of directors of the Kidney Health Initiative. Thanks for joining me, Dr Tuttle.

Katherine R. Tuttle, MD: Thank you. It's a pleasure to be here with you today.

Shubrook: Many of my patients with type 1 and type 2 diabetes have CKD. Historically, I think about screening them to see whether they have changes in glomerular filtration rate (GFR) and/or albumin excretion in the urine. Let's say I find someone with a urine albumin-to-creatinine ratio less than 300 mg/g. What are the things I should be doing to help the patient, their kidneys, and their overall mortality?

Tuttle: The first thing is good glycemic control. We know from an abundance of evidence in both type 1 and type 2 diabetes that intensification of glycemic control, especially if initiated early in the course of diabetes, sustained over time, done safely, and avoiding hypoglycemia, is the best defense against microvascular complications—particularly nephropathy, which we now call "diabetic kidney disease." That is the cornerstone of good diabetes care and prevention of complications.

Many people with diabetes also have high blood pressure—at least 75% of the general type 2 diabetes population and over 90% in patients who also develop kidney disease. In type 1 diabetes, hypertension usually occurs with onset of kidney disease. That is another clinical pearl: If you have a type 1 diabetic patient, particularly one w has had diabetes for 10 years or more, who develops hypertension, look for kidney disease if you haven't already. Blood pressure goes up when kidney function goes down.

We know that good blood pressure control also prevents the progression of kidney disease in patients with diabetes. What is good blood pressure control? That's a matter of debate now, in terms of blood pressure targets. I feel comfortable saying that once albuminuria has developed, a target less than 130/80 mm Hg is preferred—a lower target. Not quite as low as in SPRINT.^[1] We have other trials in this field that also suggest 130/80 mm Hg. Remember, SPRINT studied nondiabetic patients.

There are challenges in getting blood pressure that low, especially in patients with long-term diabetes. Many have orthostatic hypotension. Remember to check their blood pressure while they're standing, because overtreatment of blood pressure with resultant orthostatic hypotension, analogous to overtreatment of glucose complicated by hypoglycemia, can lead to short-term complications that undo the long-term benefits.

The first line of defense is a renin-angiotensin system inhibitor—either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), but not both. We did clinical trials intensifying renin-angiotensin system inhibition by combined ACE inhibition and ARBs. We found that we actually caused more harm, especially hyperkalemia, than benefit. That's another pearl. More is not better when it comes to these agents—one or the other, but not both. The standard of care is a renin-angiotensin system inhibitor.

The most exciting thing is the emerging evidence that the newer glucose-lowering agents have direct effects on the kidney that go beyond lowering of glycemia and blood pressure. That has probably been the most exciting development in the past decade in terms of both micro- and macrovascular complications.

Don't Forget the Basics

Shubrook: You brought up many really important things. Don't forget about the basics. If someone has CKD and diabetes, remember glucose and blood pressure control. Remember that we need to use something that affects the renin-angiotensin system, like an ACE or an ARB, but not together in combination, and we only start one once we have evidence of hypertension or abnormal albuminuria.

Tuttle: That's a really important point, Jay. There were studies that looked at renin-angiotensin system inhibition for the prevention of diabetic kidney disease. They don't prevent diabetic kidney disease any better than other antihypertensive agents. However, renin-angiotensin system inhibitors are specifically indicated once kidney disease develops. There is nothing wrong with using them for blood pressure control in diabetic patients, but they're not going to prevent kidney disease. On the other hand, once kidney disease develops, they are proven to be effective for slowing progression.

Shubrook: What about these new agents? There are all these new medicines. How do they help my patients with diabetes and kidney disease?

SGLT2s and GLP1s: The Evidence

Tuttle: We have been looking for better treatments for a long time, and a lot of science has been done. The cardiovascular (CV) outcome trials on sodium-glucose cotransporter-2 (SGLT2) inhibitors and, shortly thereafter, glucagon-like peptide-1 (GLP1) receptor agonists really turned the world upside down. It was almost like we had been "looking for love in all the wrong places." The CV outcome trials have truly been a gift to the diabetes community for reasons that were not anticipated.

Remember, these were done to assess safety. However, the people who designed the trials were prescient enough to build in enough statistical power that, if these drugs met the safety criteria, the trials could also assess benefit at a more rigorous statistical level. That does require a priori design, and they did it. That was probably one of the smartest things that the people who designed those trials did because, of course, in both classes of agents, CV safety was confirmed.

Both classes of agents, however, go a step beyond CV safety to CV benefit. Some specific agents reduced CV death. It was really amazing. The secondary outcomes were also gifts. The investigators had also prespecified kidney outcomes based on both GFR and albuminuria as well as clinical events.

The first trial was the EMPA-REG trial, which showed us that empagliflozin prevented CV death in patients with type 2 diabetes. Particularly, patients with heart failure had a reduction in heart failure events.^[2,3] There were also dramatic effects on the kidney. There were reductions in every kidney outcome we measure—albuminuria onset and progression. Empagliflozin prevented kidney disease and patients who had it—about one third of the EMPA-REG population—did not progress. The researchers also reported slowed GFR decline and prevention of end-stage renal disease and deaths attributed to kidney disease. Those are secondary outcomes, so we're not going to see that included on a US Food and Drug Administration (FDA) label.

Rapidly following those observations, the kidney trials started. CREDENCE is a canagliflozin study, which was done in a population of patients with type 2 diabetes selected for kidney disease, with primary kidney outcomes.^[4,5] It was stopped early, in late 2018, because of overwhelming benefit. We have not seen the data yet, but they will be reported out at the World Congress of Nephrology in April 2019.

We want to scrutinize the data, the magnitude of the benefit, and the safety, which is always paramount. In my career in nephrology, I can't remember a kidney disease trial stopped for overwhelming benefit. We have certainly had trials stopped early for safety. If the results are as promised, I think we may see a major shift in terms of recommendations to use these agents earlier in people with or at high risk for kidney disease.

With regard to the GLP1 receptor agonists, the LEADER trial was the first out of the chute.^[6] The CV benefit, interestingly enough, with liraglutide was reduction of CV death. The CV event reductions were primarily in atherosclerotic, not heart failure, events. It is very nice to have a menu of therapies, depending on the profile of the individual patient and what, as a physician, you might anticipate will be greatest risks. Similarly, in the secondary kidney outcomes, liraglutide was associated with slowed progression in albuminuria onset, increases in albuminuria, loss of glomerular filtration rate (GFR), and prevention of those same kidney endpoints.

One of the exciting clinical trials that was published in the past year was AWARD-7, which investigated dulaglutide versus insulin glargine as basal therapy for type 2 diabetes.^[7] It was the first trial of the newer glucose-lowering agents in patients with moderate to severe CKD. We found that there was a marked reduction in albuminuria and decline in estimated GFR (eGFR). In an exploratory analysis, rates of 40% eGFR decline and end-stage renal disease events were correspondingly reduced by 50%.

It is exciting that we are developing a menu of therapies. I think an important point for patients with kidney disease is that GLP1 receptor agonists can generally be used in those with eGFRs as low as 30 mL/min/1.73 m². After AWARD-7, the dulaglutide label by the FDA indicates that this GLP1 receptor agonist may be used down to a GFR of 15 mL/min/1.73 m². The drug is also associated with less hypoglycemia and weight loss, which are clear benefits.

We have a limited number of drugs that we can use for glycemic control when eGFR is low. To have GLP1 receptor agonists available to use in CKD stage 4 patients really helps because these patients usually need insulin for basal therapy and hypoglycemia is a tremendous risk. This class of antihyperglycemic agents helps us to achieve glycemic control and to avoid hypoglycemia while protecting the heart and kidneys.

Again, none of these drugs are yet labeled for kidney disease per se by regulatory agencies, but I think we can justify using the GLP1 receptor agonists for glycemic control and do it safely in patients with CKD. The emerging data suggest both CV and kidney benefits. Importantly, the CV benefits hold up in the low eGFR groups. We have to keep our eye on safety, but overall, the profile of these drugs looks good, particularly the lower rates of hypoglycemia.

Shubrook: It is a good day in diabetes. Certainly, we want to continue working to reduce both CV and microvascular complications in our patients. We have evidence that some of our glucose-lowering agents not only treat hyperglycemia but also have secondary endpoints that could be important, including the slowing of the progression of CKD.

With some of these agents, we might be able to help the kidney and help prevent hypoglycemia, which is a very common problem in our patients with advanced kidney disease.

Thank you so much for your time today. I look forward to talking to you again.

Tuttle: Thank you very much.

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