This article is part of “Innovations In: Kidney Disease,” an editorially independent special report that was produced with financial support from Vertex.
More than one in seven people in the U.S. have chronic kidney disease, which was the ninth-leading cause of death worldwide in 2023. But until recently, just one class of drugs—called renin-angiotensin system (RAS) inhibitors—had been shown to slow progression of the illness, and even those medications were only modestly effective.
For decades researchers have been investigating whether other types of medications can treat the ailment. Because kidney health is inextricably intertwined with other conditions, particularly diabetes and cardiovascular disease, it seemed possible that drugs developed for those issues might also be useful for halting kidney deterioration. Medications known as GLP-1 receptor agonists—including the blockbuster drug Ozempic—were first developed for type 2 diabetes and have since gained prominence for treating obesity and cardiovascular disease. These drugs also have begun to revolutionize treatment for chronic kidney disease.
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They’re not the only ones. A drug called finerenone, part of a drug class called mineralocorticoid receptor antagonists (MRAs), and another group of medications, inhibitors of a protein called SGLT2, also have shown success in preserving kidney function. Despite their similarities, however, each of these drug groups works differently. Today kidney specialists believe it’s possible that combined treatment with all three types, together with RAS inhibitors, could add decades to the lives of people with chronic kidney disease. Because kidney patients also often have heart problems, diabetes and obesity, the drugs have a chance of treating multiple conditions.
“For the first time there’s a realistic prospect of actually stopping kidney disease progression,” says Maarten Taal, a nephrologist at the University of Nottingham in England. And the combinations raise hope of a day when the disease could actually be reversed, he says. “That’s why these drugs are game changers, and the fact that they each work by a completely different mechanism implies that they will have an additive effect because they’re not all doing the same thing.”
Researchers began to identify the mechanisms that drive progressive kidney damage in the 1980s. No matter the cause—diabetes, high blood pressure, glomerulonephritis, autoimmune conditions, or something else—all kidney disease progresses over time, so scientists hypothesized that there must be common underlying processes. If they could find and inhibit those things, they could build therapies to treat a broad range of kidney diseases, Taal says. They discovered that a hormone called angiotensin was a “master regulator of the whole process,” he says. Angiotensin can constrict blood flow, prompt people to increase salt and water intake, and retain more of those substances in their kidneys. It is often overactive in people with kidney disease. Scientists therefore developed RAS inhibitors that curb the production of angiotensin or its actions in the kidneys.
RAS inhibitors can reduce the risk of kidney disease by 15 to 50 percent, but they aren’t enough. “Although they slowed progression, they didn’t halt it,” Taal says, and they didn’t work in everyone.
Scientists returned to the drawing board, but success remained elusive. “We had 15 years during which there was just no progress. All sorts of other therapies were tried and found ineffective,” Taal says. Nothing seemed to work.
Then, in 2019, results of a trial of an SGLT2 inhibitor drug called canagliflozin were presented at a conference. They were impressive enough that audience members stood up and clapped. The medication, initially approved in 2013 for type 2 diabetes, was the first SGLT2 inhibitor shown to protect the kidneys. The trial showed those who took the drug had much lower levels of creatinine protein in the blood (a sign of kidney damage). Death from renal or cardiovascular causes was also reduced, as was end-stage kidney disease, which meant fewer people needed dialysis or transplants. “The trial was stopped early because of its benefit,” Taal says.
All the participants in that trial had type 2 diabetes. But the next SGLT2 inhibitor tested—dapagliflozin, in 2020—showed a similar benefit in kidney function in people without diabetes. Empagliflozin followed in 2022.
The empagliflozin trial was crucial because it included people at lowest risk, those who had low levels of albumin protein in their urine. (Albumin is another sign of kidney damage.) “That trial showed benefit across basically the entire spectrum of people with and without albuminuria,” says David Cherney, a nephrologist at the University of Toronto.
The protein that SGLT2 inhibitors block moves glucose and sodium in the kidneys back into the blood. By preventing glucose from being reabsorbed, SGLT2 inhibitors force more of it to exit the body through urine, reducing overall blood glucose and modestly reducing body weight.
There was another benefit as well. “You’re also blocking the reabsorption of some sodium,” Taal says. Not only does that lower blood pressure, but it also helps to restore the kidneys’ natural-feedback system for glomerular filtration. And SGLT2 inhibitors reduce pressure in the small blood vessels that filter out waste in the kidneys, thereby reducing stress and cell injury in them.
Lowering blood pressure in the kidney eases the physical force that pushes protein into urine, Cherney says, “and by reducing that pressure, it also reduces the mechanical distortion, distension and wall stress on the layers of cells that protect the kidney.” This decrease, in turn, lessens the force responsible for fibrosis, a buildup of scar tissue that harms organs.
In combination with RAS inhibitors, SGLT2 inhibitors cut the risk of kidney disease progression by about an additional 30 percent. Taal says the evidence shows most people with chronic kidney disease should take them. One study predicted that in people with early-stage chronic kidney disease, adding SGLT2 inhibitors to an existing regimen of RAS inhibitors could increase the life of their kidneys by more than 20 years. “It’s a game changer,” he says.
“We need to up our game. Instead of just hoping to stop kidney disease progression, we need to try to reverse the process.” —Maarten Taal University of Nottingham
The next drug to shift the landscape of chronic kidney disease came from attempts to halt or reduce fibrosis in heart failure patients. Finerenone emerged as a prominent antifibrosis candidate and was approved for chronic kidney disease in 2021 after a pair of studies showed it improved cardiovascular outcomes and reduced the risk of kidney disease progression.
Finerenone’s mechanism differs from those of both SGLT2 inhibitors and GLP-1 receptor agonists, so researchers were keen to know how the drugs might work when taken together. The results of a study published in the New England Journal of Medicine last summer, testing the combination of finerenone and empagliflozin, have begun to answer that question, and it’s good news. “The effects are additive, so if you get both, you get about double the benefit of one or the other,” Taal says. “And again, that’s all on top of being on a RAS inhibitor.”
The exploration of GLP-1 receptor agonists followed. Initially developed to treat type 2 diabetes, the drugs provided benefits in weight loss and cardiovascular health that led to a randomized trial investigating potential kidney benefits. The trial showed that semaglutide—the GLP-1 receptor agonist used in Ozempic and Wegovy—reduced risks of kidney failure and renal or cardiovascular death.
It was the first study big enough to show that diabetes patients taking GLP-1 receptor agonists were less likely to end up on dialysis, need a kidney transplant or go into renal failure, says Mark Cooper, an endocrinologist at Monash University in Melbourne. Then came another study, called SELECT, which “confirmed this can occur even in the absence of diabetes,” he says.
SELECT was a large study focused on obesity and cardiovascular disease in people without type 2 diabetes, but it included kidney outcomes as a secondary end point. The data showed that semaglutide reduced the progression of kidney disease by 22 percent across all subgroups of people enrolled.
More trials are now underway to look at not only GLP-1 receptor agonists but also other gut hormones, including GIP. Tirzepatide, the active ingredient in the drugs Mounjaro and Zepbound, is a hormone analogue designed to act on GIP and GLP-1 receptors. One ongoing trial is examining tirzepatide’s effects on kidneys. Its results may show whether this kind of dual GIP and GLP-1 receptor agonist has different outcomes than GLP-1s alone.
Meanwhile some of the ongoing GLP-1 trials are aimed at understanding how these drugs benefit the kidneys. What scientists know so far is that GLP-1s are part Swiss Army knife and part black box: There are at least a dozen or so hypothesized mechanisms for how they’re improving overall metabolic health and protecting organs across multiple body systems, but there’s a lot researchers still don’t know. “We don’t have a really comprehensive, detailed understanding for most of what GLP-1 does,” says Daniel Drucker, an endocrinologist at the University of Toronto. “The indirect mechanisms of weight loss, blood pressure control, reduced lipids and reduced inflammation may contribute,” as may blood sugar control, he says.
“But that’s definitely not the whole story,” Taal says. Other potential mechanisms include increasing insulin production, increasing sodium excretion and decreasing inflammation. And recent data from a trial that Cherney is involved in, called REMODEL, show that semaglutide reduces damage to kidney blood vessel linings, decreases the activity of natural killer cells (white blood cells that destroy diseased cells), and increases fat loss from stores surrounding the kidneys. “The fat around the kidney is very metabolically active, angry and inflammatory fat,” Cherney says. Getting rid of some of that fat may lead to the other improvements.
None of these drugs will be effective, however, if people don’t know they have chronic kidney disease in the first place, something that applies to huge swaths of the population. So alongside the development of all these new drugs, nephrologists have been thinking about ways to increase awareness about chronic kidney disease so more people can begin benefiting from these medications, says Giovanni Strippoli, a nephrologist at the University of Bari in Italy.
People know that obesity and cardiovascular disease are serious health problems. “Chronic kidney disease is just as big,” Strippoli says. The problem is that the general medical community, beyond nephrologists, hasn’t really grasped the extent of the problem. If that awareness can be improved, with broader screening and diagnosis, and if these new drugs can be made available to everyone who needs them, “we can substantially reduce the burden of chronic kidney disease and prevent many of its most serious consequences,” he says. “The armamentarium in the hands of a practicing nephrologist today is substantially improved. When you have more weapons, it’s a lot easier to deal with a problem that is a potential killer.”
In a big step forward, the World Health Organization recently listed chronic kidney disease as a major public health priority. The next step will be figuring out appropriate combinations of the new drugs and determining how much those combinations slow disease progression or whether they might even halt it. Because the newer drugs were all developed around the same time, there are not yet trials investigating simultaneous doses of all four classes—RAS inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, and MRAs such as finerenone.
“If you can get people to be delayed from dialysis by 10 years or even half that, that’s still an unbelievable victory,” Cherney says. Some of his patients receiving these therapies have improved to the point where urine tests show no protein, indicating that blood vessels in the kidneys have healed. Treatments that effective didn’t exist before, Cherney says.
“We need to up our game,” Taal says. “Instead of just hoping to stop kidney disease progression, we need to try to reverse the process.” Evidence suggests that’s biologically possible, he asserts, but until enough people with kidney disease have been tested on all four available drug classes, it will remain an open question. Cooper is hopeful there will be a positive answer. Researchers used to believe kidney injury “was inexorable—would just go on forever,” he says. But now “we’ve been able to change [its] natural history. Now we believe you can repair a kidney.”
