Experimental strategies that reduce cell death or reverse epigenetic changes in kidney cells are being studied to help protect the kidneys in patients with diabetes.
Treatment options for diabetic kidney disease have grown in recent years with the availability of 2 new classes of drugs, the sodium-glucose cotransporter 2 inhibitors (SGLT2) and the glucagon-like peptide 1 agonists (GLP1), noted a recent review in Nature Reviews Nephrology. These agents help lower a patient’s blood sugar levels and are used alongside renin angiotensin system inhibitors (RAS) and other traditional diabetes management methods.
Mark Cooper, PhD, head of the department of diabetes at Monash University in Melbourne, Australia, noted that the hotly awaited final results of the CREDENCE trial of the SGLT2 inhibitor canagliflozin, which was stopped early in July 2018 because the kidney benefits for patients were positive, may seal the role of these drugs in clinical care. Cooper co-authored the review in Nature Reviews Nephrology.
Additionally, results from the AWARD-7 trial showed the GLP1 agonist dulaglutide helped control blood sugar and slow kidney decline in patients with diabetes.
Now, ongoing studies are exploring additional approaches that also help slow kidney damage caused by diabetes. One such approach aims to block an enzyme called apoptosis signal regulating kinase 1 (ASK1) and has entered clinical trials. Another, which is still being explored in animal studies, seeks to reverse epigenetic changes that may contribute to the loss of podocytes and kidney function. While these emerging strategies remain years from the clinic, they add to optimism that future therapies for kidney disease may better preserve kidney function.
“It is an exciting time for diabetic kidney disease; it looks like the SGLT inhibitors will turn out to be proven and then there’s quite a few promising add-ons like the GLP1 agonist and then the ASK1 inhibitors,” Cooper said. “If they turn out to deliver, you’ve actually got evidence that diabetic kidney disease [DKD] can really be treated, because, until now, they are really just trying to slow it down.”
SGLT2 inhibitors
The CREDENCE trial results presented at the 2019 World Congress of Nephrology in Melbourne in April showed that canagliflozin reduced the risk of a composite of end-stage kidney disease, doubling of serum creatinine, or death from kidney or cardiovascular disease by 30% in patients with type 2 diabetes compared to placebo. The results were published simultaneously in the New England Journal of Medicine.
“Canagliflozin is the first medical breakthrough in nearly 20 years proven to slow the progression of chronic kidney disease in patients with diabetes at high risk of developing kidney failure,” stated lead author Vlado Perkovic, MBBS, PhD, executive director of the George Institute for Global Health in Australia, in a press release from the drug’s maker Johnson & Johnson. “These impressive results from the CREDENCE study have significant clinical implications for preventing kidney failure and improving health for millions of people living with chronic kidney disease and type 2 diabetes.”
Despite the excitement about SGLT2 inhibitors, some safety issues have arisen in patients being treated with the SGLT2 inhibitors currently approved by the US Food and Drug Administration (FDA). The FDA issued a warning about the risk of severe genital infections in patients treated with SGLT2 inhibitors for diabetes. Between 2013 and 2018, the agency identified 12 cases of Fournier’s gangrene in patients taking a SGLT2 inhibitor. Though these cases are rare, the agency recommends patients seek immediate medical care if they develop a tenderness, redness, or swelling of the genitals and a fever over 100.4 F°. They suggest physicians start treatment with broad spectrum antibiotics immediately if such an infection is suspected.
More recently in March, the FDA declined to approve another SGLT2 inhibitor, sotagliflozin, according to the drug’s maker Sanofi. In January, an FDA advisory committee vote on whether to recommend the drug’s approval ended in an 8 to 8 tie, in part owing to concerns about the risk of diabetic ketoacidosis in patients taking the drug.
ASK1 inhibitors
Managing hypertension using drugs like angiotensin converting enzyme (ACE) inhibitors helps protect the kidneys of patients with diabetes. But these drugs target just one part of the damage that occurs. Other important contributors to diabetes-related kidney damage are inflammation, cell death, and scarring or fibrosis.
To reduce these effects, scientists are studying a drug that stops apoptosis signal-regulating kinase 1 (ASK1), an enzyme that sets off a cascade of these harms. A team of researchers from Gilead Sciences showed that an experimental drug called GS-444217 that inhibits ASK1 reduces cell death and fibrosis in rodents with conditions similar to human DKD. The treatment also stopped the decline in glomerular filtration rates and decreased proteinuria. Combining this ASK1 inhibitor with an ACE inhibitor led to even better results.
“Combining ASK1 inhibition with RAAS inhibitors is an attractive combination for [DKD or chronic kidney disease] because these biological pathways are distinct and our current results demonstrate that ASK1 inhibition can provide additional benefits when administered concomitantly with ACE inhibitors,” said the study’s lead author, John Liles, PhD, director of biology at Gilead Sciences.
“It’s a completely novel pathway,” Cooper said. He noted such drugs would likely be used in combination with existing DKD therapies.
Results of a phase 2 clinical trial of the ASK1 inhibitor Selonsertib compared with placebo that enrolled 334 patients didn’t meet its primary endpoint (Kidney Week 2018) (Abstract: TH-PO1148). Unexpectedly, the drug temporarily reduced creatinine clearance, but according to abstract authors post hoc analyses suggest the drug slows DKD progression in the longer term. The company is planning a phase 3 trial of the drug.
“There is an urgent unmet need for novel agents to slow progression of kidney disease and prevent kidney failure,” said Liles. “Current treatments primarily target glomerular hemodynamics; however, there are no treatments that target apoptosis, inflammation, and fibrosis in the kidney.”
Epigenetic protection
Patients with diabetes who are exposed to high blood sugar levels early in the course of their disease remain at increased risk for complications like diabetic kidney disease, even after treatment brings their blood sugar under better control, said endocrinologist Andrew Advani, MD, PhD, an associate professor and clinician scientist at St. Michael’s Hospital in Toronto and the University of Toronto. This suggests that a “metabolic memory” persists, and some pioneering studies suggest that high blood sugar may cause lasting epigenetic changes that alter which genes are turned on and off.
“It’s been proposed that epigenetic mechanisms may underlie the cellular basis of metabolic memory because epigenetic processes provide a means by which a transient environmental insult can have a long-lasting cellular effect,” Advani explained.
That idea led Advani and his colleagues to question whether these epigenetic changes can be stopped or reversed to prevent diabetes complications in the kidney. They looked specifically at proteins called histones. DNA strands wind around histones to enable DNA to be packed inside the nucleus of a cell. The way in which these histones are modified by enzymes can help control which genes are turned on and off within a cell. Advani noted that histone-modifying drugs are already being used in cancer treatment.
In a 2018 study, Advani and colleagues showed that a histone modification called H3K27me3 turns off nearby developmental genes that aren’t needed in adult kidneys. This helps protect key glomerular cells called podocytes from regressing into a less developed state. Advani and his colleagues have found that H3K27me3 is lost in mice with chronic kidney disease leaving them vulnerable to kidney damage. They also looked at samples from human patients with diabetic kidney disease and found they too lose this epigenetic mark and have a reactivation of developmental genes.
“Our work is important because it shows that histone modifications contribute to the natural history of chronic kidney diseases, and that it is possible to therapeutically manipulate histone modifications and alter the natural history of diabetes complications, particularly kidney disease,” Advani said.
In animal experiments, they tested an experimental compound called GSK-J4 that protects these epigenetic marks. The experimental treatment slowed the development of kidney disease in mice with diabetic kidney disease and another form of kidney disease, focal segmental glomerulosclerosis. More research is needed to determine whether such a treatment would work in patients with kidney disease and which patients would benefit, Advani said.
Cooper thought it is possible the epigenetic therapies may prove useful in kidney disease, as they have in cancer. But he cautioned that the study of drugs that affect histone modifications is at a much earlier stage than the ASK1 inhibitors. Epigenetic mechanisms are at work throughout the body, so the drugs may have effects elsewhere, Advani noted. Cooper said off-target effects of epigenetic treatments are likely and that substantial safety testing will be necessary to understand potential effects on other parts of the body and whether they would be tolerable for a long duration of treatment.
“With cancer you’re willing to take a higher risk profile, but I think for a condition like chronic kidney disease the concern is off-target effects,” Cooper said. Cooper noted, however, that some off-target effects may actually be beneficial and help counter other diabetes complications. For example, these epigenetic mechanisms might also contribute to diabetic retinopathy or heart disease, and the drugs targeting them may also benefit these complications.
“We don’t know at this stage whether a treatment that targets these kinds of processes is going to be feasible in chronic long-term diseases like diabetic kidney disease where side effect profiles need to be favorable,” Advani said. “But studying the roles that epigenetics play in kidney disease could open up new therapeutic opportunities in the future.”
